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Letter   |    
Intravenous Valproate for Rapid Stabilization of Agitation in Neuropsychiatric Disorders
Donald M. Hilty, M.D.; Gerardo D. Rodriguez, M.D.; Robert E. Hales, M.D., M.B.A.
The Journal of Neuropsychiatry and Clinical Neurosciences 1998;10:365-366.
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Tourette's SyndromeAcute Disseminated EncephalomyelitisLyme DiseaseSyphilisSchizophreniaBrain ImagingLacuna, CerebralValproateAgitationAutism

SIR: We report the use of intravenous valproate for the treatment of acute behavioral agitation in a patient with autism.

Autistic disorder is a pervasive developmental disorder with essential features of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interests.1 Behavioral disorders associated with autistic disorder include hyperactivity, aggressiveness, and self-injurious behavior.

A variety of psychotropic medications have been used as part of a multidisciplinary treatment plan for behavioral agitation in children with autistic disorder. A survey of 838 care providers for autistic patients reported that neuroleptics (12.2%), antidepressants (6.1%), mood stabilizers (3.9%), stimulants (6.6%), sedative/hypnotics (6.3%), and opiate blockers (0.4%) are the most commonly used psychotropic medications.2 No systematized research has been conducted on these medications for the management of acute or chronic behavioral agitation in patients with autistic disorder.3

Acute behavioral agitation necessitates rapid tranquilization by intramuscular (IM) or intravenous (IV) medication, usually haloperidol and a benzodiazepine such as lorazepam. Haloperidol is clinically efficacious, but it is limited by side effects including acute dystonic reaction, sedation, hypotension, and potential cardiac problems.4 On the other hand, benzodiazepines produce significant cognitive side effects, ataxia, and increased agitation.

Valproate is a standard treatment for epilepsy, migraine headaches, and acute mania of bipolar disorder. It has also been used for the treatment of behavioral agitation associated with mental retardation (with and without comorbid mania)3 and dementia.5

Several lines of evidence led us to hypothesize that valproate might be a useful treatment for behavioral agitation associated with autistic disorder. First, data suggest that valproate may have anti-aggression properties in human studies.6 Second, valproate enhances central GABAergic neurotransmission by inhibiting GABA catabolism, stimulating GABA synthesis, and potentiating GABA's postsynaptic effects.7 Finally, valproate administered to patients with mania is known to increase central serotonin transmission,8 and in rats it significantly elevates serotonin;9 these results are of interest because hyposerotonergic states are associated with impulsive behavior and agitation.

Intravenous valproate (Depacon, Abbott Laboratories, Abbott Park, IL) may be infused for status epilepticus without altering consciousness or causing pulmonary suppression, arrhythmias, and tissue necrosis. The dose and pharmacokinetics of IV valproate are identical to the oral and rectal routes of administration. The most common side effects of IV valproate include dizziness, headache, nausea, injection site pain, injection site reaction (not necrosis), taste perversion, somnolence, and vomiting; these occur in less than 2% of patients. IV valproate has been administered at rates of 1,000 mg/60 min to 1,000 mg/5 min in healthy volunteers with no serious adverse events,10 although the package insert recommends that 500 mg valproate be diluted with 5% dextrose, sodium chloride, or lactate ringers and infused over 60 minutes.

An 8-year-old Caucasian female with autistic disorder per DSM-IV criteria has been followed for 6 years for behavioral agitation. Her birth and developmental history were unremarkable until 2 years of age. There were no significant findings on laboratory tests (including fragile X testing at age 7), neurological evaluation, EEG, or imaging studies. Her ongoing medications included risperidone 2 mg po bid and benztropine 1 mg po bid. Past trials of typical neuroleptics, methylphenidate, clonidine, and naltrexone were ineffective.

The most recent episode of agitation necessitated a call to paramedics to transport the patient to the emergency room. On the Overt Aggression Scale (OAS),11 she met 0 of 4 criteria for verbal aggression, 1 of 4 criteria for physical aggression against objects, 3 of 4 criteria for physical aggression toward herself, and 3 of 4 criteria for physical aggression toward others. Her overall score on the OAS was 28. Interventions included talking to the patient, holding the patient, and the use of physical restraints. Including IV valproate as mentioned below, the OAS intervention score was 13. The family provided consent for intravenous valproate administration. A dose of 2,000 mg of valproate was infused over a 10-minute period. Since the patient's weight was 53 kg, this was a rate of approximately 40 mg/kg per 10 minutes. The patient's behavior decreased to 0 of 4 on all scales within 15 minutes, and she suffered no side effects, obviating the need for hospitalization. Valproate 1,000 mg po bid was added to her routine medications the next morning. Over the next 6 months, her usual aggressive behavior and intervention scores on the OAS decreased to 10 and 4, respectively, compared with 33 and 8 during the 6 months prior to valproate treatment.

In summary, intravenous valproate was effective for this patient with autistic disorder, for both acute and chronic behavioral agitation. Controlled clinical trials are needed to document whether intravenous valproate may be effective to treat agitation in children and adults.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC, American Psychiatric Association, 1994
 
Aman MG, van Bourgondien ME, Wolford PL, et al: Psychotropic and anticonvulsant drugs in subjects with autism: prevalence and patterns of use. J Am Acad Child Adolesc Psychiatry  1995; 34:1672—1681
[CrossRef] | [PubMed]
 
Gilman JT, Tuchman RF: Autism and associated behavioral disorders: pharmacotherapeutic intervention. Ann Pharmacother  1995; 29:47—56
[PubMed]
 
Dubin WR: Rapid tranquilization: antipsychotics or benzodiazepines? J Clin Psychiatry 1988; 48(suppl):5—11
 
Alexopoulos GS, Silver JM, Kahn DA, et al: The expert consensus guideline series: treatment of agitation in older persons with dementia. J Clin Psychiatry (in press)
 
Mazure CM, Druss BG, Cellar JS: Valproate treatment of older psychotic patients with organic mental syndromes and behavioral dyscontrol. J Am Geriatr Soc  1992; 40:914—916
[PubMed]
 
Lott AD, McElroy SL, Keys MA: Valproate in the treatment of behavioral agitation in elderly patients with dementia. J Neuropsychiatry Clin Neurosci  1995; 7:314—319
[PubMed]
 
Maes M, Calabrese J, Jayathilake K, et al: Effects of subchronic treatment with valproate on l-5-HTP-induced cortisol responses in mania: evidence for increased central serotonergic neurotransmission. Psychiatry Res  1997; 71:67—76
[CrossRef] | [PubMed]
 
Biggs CS, Pearce BR, Fowler LJ, et al: Regional effects of sodium valproate on extracellular concentrations of 5-hydroxytryptamine, dopamine, and their metabolites in the rat brain: an in vivo microdialysis study. J Neurochem  1992; 59:1702—1708
[CrossRef] | [PubMed]
 
Hussein Z, Patterson KJ, Lamm JE, et al: Effect of infusion duration on valproate pharmacokinetics. Biopharm Drug Dispos  1993; 14:389—399
[CrossRef] | [PubMed]
 
Silver JM, Yudofsky SC: The Overt Aggression Scale: overview and guiding principles. J Neuropsychiatry Clin Neurosci 1991; 3(suppl):S22—S29
 
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References

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Washington, DC, American Psychiatric Association, 1994
 
Aman MG, van Bourgondien ME, Wolford PL, et al: Psychotropic and anticonvulsant drugs in subjects with autism: prevalence and patterns of use. J Am Acad Child Adolesc Psychiatry  1995; 34:1672—1681
[CrossRef] | [PubMed]
 
Gilman JT, Tuchman RF: Autism and associated behavioral disorders: pharmacotherapeutic intervention. Ann Pharmacother  1995; 29:47—56
[PubMed]
 
Dubin WR: Rapid tranquilization: antipsychotics or benzodiazepines? J Clin Psychiatry 1988; 48(suppl):5—11
 
Alexopoulos GS, Silver JM, Kahn DA, et al: The expert consensus guideline series: treatment of agitation in older persons with dementia. J Clin Psychiatry (in press)
 
Mazure CM, Druss BG, Cellar JS: Valproate treatment of older psychotic patients with organic mental syndromes and behavioral dyscontrol. J Am Geriatr Soc  1992; 40:914—916
[PubMed]
 
Lott AD, McElroy SL, Keys MA: Valproate in the treatment of behavioral agitation in elderly patients with dementia. J Neuropsychiatry Clin Neurosci  1995; 7:314—319
[PubMed]
 
Maes M, Calabrese J, Jayathilake K, et al: Effects of subchronic treatment with valproate on l-5-HTP-induced cortisol responses in mania: evidence for increased central serotonergic neurotransmission. Psychiatry Res  1997; 71:67—76
[CrossRef] | [PubMed]
 
Biggs CS, Pearce BR, Fowler LJ, et al: Regional effects of sodium valproate on extracellular concentrations of 5-hydroxytryptamine, dopamine, and their metabolites in the rat brain: an in vivo microdialysis study. J Neurochem  1992; 59:1702—1708
[CrossRef] | [PubMed]
 
Hussein Z, Patterson KJ, Lamm JE, et al: Effect of infusion duration on valproate pharmacokinetics. Biopharm Drug Dispos  1993; 14:389—399
[CrossRef] | [PubMed]
 
Silver JM, Yudofsky SC: The Overt Aggression Scale: overview and guiding principles. J Neuropsychiatry Clin Neurosci 1991; 3(suppl):S22—S29
 
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