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CLINRESREPORT   |    
A Pilot Study of Quetiapine Treatment of Aggression Due to Traumatic Brain Injury
Edward Kim, M.D., M.B.A.; Mona Bijlani, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2006;18:547-549.
View Author and Article Information

Received September 7, 2005; revised December 6, 2005; accepted December 30, 2005. Dr. Kim is Clinical Associate Professor of Psychiatry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, and Associate Director of Neuroscience Medical Strategy, Bristol-Myers Squibb Company, Plainsboro, New Jersey. Dr. Bijlani is Assistant Professor of Psychiatry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey. Address correspondence to Dr. Kim, Associate Professor of Psychiatry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 671 Hoes Lane, Piscataway, NJ 08855-1392; edward.kim@bms.com (E-mail).

Copyright © 2006 American Psychiatric Publishing, Inc.

In a 6-week open-label, flexible dose pilot study of quetiapine for treatment of aggression secondary to traumatic brain injury (TBI), seven subjects who were at least 3-months post-injury were enrolled. The Overt Aggression Scale — Modified (OAS-M) and Clinical Global Impression (CGI) were primary outcome measures. Administration of quetiapine at doses of 25 to 300mg daily was efficacious and well-tolerated in reducing irritability and aggression resulting from TBI, with an associated improvement in cognitive functioning.

Abstract Teaser
Figures in this Article

Traumatic brain injury accounts for approximately one million emergency room visits and 500,000 hospitalizations in the United States each year.1 Agitation and aggression complicate the postinjury recovery of up to 71% of traumatic brain injury (TBI) patients2 and can lead to substantial psychosocial impairment and a failure to access or benefit from neurorehabilitation services.3 Atypical antipsychotic agents have demonstrated efficacy in the reduction of impulsive aggression in schizophrenia and other conditions.46 This prospective, open-label study was designed to provide preliminary data on the efficacy and tolerability of quetiapine in the treatment of TBI-induced aggression.

This 6-week, flexible-dose, open-label study was approved by the Institutional Review Board of the Robert Wood Johnson Medical School. Subjects were required to be at least 3 months post-injury, medically stable, and residing in a noninstitutional setting. Irritability and aggression, or a score of at least 15 on the Overt Aggression Scale Modified for Outpatients (OAS-M),7 must have started after the index injury and persisted for a minimum of 1 month prior to screening. Subjects with a pre-injury history of recurrent impulsive aggression, a pre-injury diagnosis of schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder, were excluded. Drug or alcohol abuse within 1 month of screening, or concomitant use of antipsychotics, lithium, or psychostimulants, were additional exclusionary criteria. Subjects were permitted to remain on antidepressants, benzodiazepines, or anticonvulsants if the doses had not been adjusted for 2 months prior to enrollment and aggression persisted.

The primary efficacy measures were the OAS-M and the Clinical Global Impression (CGI). A secondary outcome measure was the Neurobehavioral Functioning Inventory (NFI).8 Tolerability measures included the Simpson-Angus Scale, Barnes Akathisia Rating Scale, Abnormal Involuntary Movements Scale, and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).9 We administered a regimen of quetiapine, 50—100mg daily in bedtime doses for the first week, then titrated every 3 to 4 days as tolerated in single doses to a maximum of 800mg daily by the end of the third week. This was followed by a maintenance phase of 3 weeks during which the dose could be adjusted based on clinical need and tolerability.

Statistical analysis for outcome variables consisted of paired t tests. In cases where data were missing, a last observation carried forward (LOCF) analysis was used.

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Subject Characteristics

Subjects included four men and three women, mean age=48.9 years (SD=2.4), with a mean time since injury of 23.1 months (SD=15.9). All subjects had sustained closed head injuries. Two of the subjects had severe injuries that resulted in a coma (5 and 20 days, respectively) and intracranial hemorrhage. Of these, only one had residual neurological impairment. None of the subjects developed postinjury seizure disorders. All subjects scored at or below the 25th percentile on baseline RBANS assessment, with a mean total scale score of 75.4 (SD=14.1), corresponding to the 5th percentile.

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Outcome Measures

Quetiapine dose ranged from 25 to 300mg daily, with a mean of 110.7mg (SD=93.4). Subjects experienced a mean reduction in OAS score of 84.5% (p=0.002). The CGI severity scale improved from a mean of 4.14 (SD=0.38) to 2.29 (SD=1.11) (p=0.002). Final assessments on the NFI were not completed in two subjects. LOCF analysis demonstrated significant improvements in the Aggression subscale (p=0.036).

Sedation was reported in three (42.8%) patients. In two cases it resolved by Week 3; in one case it did not resolve until Week 6. No discontinuations were attributed to sedation. The Simpson Angus Scale and Barnes Akathisia Scale revealed mild extrapyramidal side effects and akathisia in one subject. There were no treatment-emergent impairments in cognitive functioning. Overall scale scores on the RBANS indicated a mean improvement of 8.02% (p=0.027).

Neurobehavioral complications of TBI are a significant source of distress and dysfunction in patients and caregivers alike. Traditional antipsychotic agents such as haloperidol and chlorpromazine have been used to successfully control such agitation.10 However, side effects of cognitive impairment and extrapyramidal side effects complicate the use of such medications in the TBI population.11,12 Quetiapine is well tolerated and effective in reducing aggression in nonpsychotic syndromes, such as pervasive developmental disorder13 and Alzheimer’s disease.5 In this study, the administration of quetiapine in doses of 25mg to 300mg daily was well-tolerated and led to significant reductions in aggression and irritability. The use of atypical antipsychotics in post-TBI psychiatric disorders has been limited to treatment of post-TBI psychosis14,15 and post-TBI delirium with delusions.16,17 This is the first prospective study of an atypical antipsychotic medication used to treat aggression following TBI in postacute patients.

Cognitive function was not only preserved, but actually improved slightly in the study cohort. Practice effect is an unlikely cause due to the fact that subjects took different versions of the RBANS at baseline and endpoint. While treatment of schizophrenia with atypical antipsychotics has led to improved cognitive performance in some studies,1820 these studies generally involved either head to head or crossover designs using conventional antipsychotics as the control or baseline treatment. As a result, no conclusions can be drawn regarding any direct effect of these medications on cognition in treatment-naïve patients. One possible explanation for the improvements may be that a reduction in psychiatric symptom intensity reduced the distracting effects of these symptoms on cognitive test performance. Anxiety and depression were not specifically monitored in this protocol, but these are known to affect neuropsychological test performance.21,22 The clinical relevance of the observed cognitive improvement has not been established, since performance on neuropsychological testing has not reliably correlated with functional improvements.23,24

This study is limited by its open-label noncontrolled design, although the robust response suggests a real therapeutic benefit from treatment. The small sample size also limits the generalizability of findings. The dosage of quetiapine was very low and never achieved the minimal labeled threshold of 400mg daily, although treatment response was substantial even at such low doses. Larger, double-blind studies are warranted to further elucidate the efficacy and tolerability of psychotropic medications in the treatment of TBI-related agitation and aggression.

This study was supported by an investigator-initiated research grant from AstraZeneca.

.
Kraus JF, McArthur DL: Incidence and prevalence of, and costs associated with, traumatic brain injury, in Rehabilitation of the Adult and Child with Traumatic Brain Injury, 3rd ed. Edited by Rosenthal M, Griffith ER, Kreutzer JS, et al. Philadelphia, FA Davis Company, 1999, pp 3—18
 
.
Silver JM, Yudofsky SC, Anderson KE: Aggressive disorders, in Textbook of Traumatic Brain Injury. Edited by Silver JM, McAllister TW, Yudofsky SC. Washington, DC, American Psychiatric Publishing, 2005, pp 259—277
 
.
Alderman N, Knight C, Henman C: Aggressive behaviour observed within a neurobehavioural rehabilitation service: utility of the OAS-MNR in clinical audit and applied research. Brain Inj 2002; 16:469—489
 
.
Volavka J, Czobor P, Nolan K, et al: Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychopharmacol 2004; 24:225—228
 
.
Scharre DW, Chang SI: Cognitive and behavioral effects of quetiapine in Alzheimer disease patients. Alzheimer Dis Assoc Disord 2002; 16:128—130
 
.
Walker C, Thomas J, Allen TS: Treating impulsivity, irritability, and aggression of antisocial personality disorder with quetiapine. Int J Offender Ther Comp Criminol 2003; 47:556—567
 
.
Yudofsky SC, Silver JM, Jackson W, et al: The overt aggression scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986; 143:35—39
 
.
Kreutzer J, Seel R, Marwitz J: Neurobehavioral Functioning Inventory. San Antonio, Harcourt Assessment, 1999
 
.
Randolph C: RBANS: Repeatable Battery for the Assessment of Neuropsychological Status. San Antonio, Harcourt Assessment, 1998
 
.
Sandel ME, Olive DA, Rader MA: Chlorpromazine-induced psychosis after brain injury. Brain Inj 1993; 7:77—83
 
.
Rao N, Jellinek HM, Woolston DC: Agitation in closed head injury: haloperidol effects on rehabilitation outcome. Arch Phys Med Rehabil 1985; 66:30—34
 
.
Stanislav SW: Cognitive effects of antipsychotic agents in persons with traumatic brain injury. Brain Inj 1997; 11:335—341
 
.
Corson AH, Barkenbus JE, Posey DJ, et al: A retrospective analysis of quetiapine in the treatment of pervasive developmental disorders. J Clin Psychiatry 2004; 65:1531—1536
 
.
Schreiber S, Klag E, Gross Y, et al: Beneficial effect of risperidone on sleep disturbance and psychosis following traumatic brain injury. Int Clin Psychopharmacol 1998; 13:273—275
 
.
Burke JG, Dursun SM, Reveley MA: Refractory symptomatic schizophrenia resulting from frontal lobe lesion: response to clozapine. J Psychiatry Neurosci 1999; 24:456—461
 
.
Temple MJ: Use of atypical anti-psychotics in the management of post-traumatic confusional states in traumatic brain injury. J R Army Med Corps 2003; 149:54—55
 
.
Krieger D, Hansen K, McDermott C, et al: Loxapine versus olanzapine in the treatment of delirium following traumatic brain injury. Neurorehabilitation 2003; 18:205—208
 
.
Bilder RM, Goldman RS, Volavka J, et al: Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159:1018—1028
 
.
Harvey PD, Meltzer H, Simpson GM, et al: Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia. Schizophr Res 2004; 66:101—113
 
.
Kivircik Akdede BB, Alptekin K, et al: Effects of quetiapine on cognitive functions in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:233—238
 
.
Eysenck MW: Anxiety and cognitive functioning: a multifaceted approach, in Perspectives of Cognitive Neurosciences. Edited by Lister RG, Weingartner HJ. New York, Oxford University Press, 1991
 
.
Massman PJ, Delis DC, Butters N, et al: The subcortical dysfunction hypothesis of memory deficits in depression: neuropsychological validation in a subgroup of patients. J Clin Exp Neuropsychol 1992; 14:687—706
 
.
Quemada JI, Munoz Cespedes JM, Ezkerra J, et al: Outcome of memory rehabilitation in traumatic brain injury assessed by neuropsychological tests and questionnaires. J Head Trauma Rehabil 2003; 18:532—540
 
.
Leahy BJ, Lam CS: Neuropsychological testing and functional outcome for individuals with traumatic brain injury. Brain Inj 1998; 12:1025—1035
 
+

References

.
Kraus JF, McArthur DL: Incidence and prevalence of, and costs associated with, traumatic brain injury, in Rehabilitation of the Adult and Child with Traumatic Brain Injury, 3rd ed. Edited by Rosenthal M, Griffith ER, Kreutzer JS, et al. Philadelphia, FA Davis Company, 1999, pp 3—18
 
.
Silver JM, Yudofsky SC, Anderson KE: Aggressive disorders, in Textbook of Traumatic Brain Injury. Edited by Silver JM, McAllister TW, Yudofsky SC. Washington, DC, American Psychiatric Publishing, 2005, pp 259—277
 
.
Alderman N, Knight C, Henman C: Aggressive behaviour observed within a neurobehavioural rehabilitation service: utility of the OAS-MNR in clinical audit and applied research. Brain Inj 2002; 16:469—489
 
.
Volavka J, Czobor P, Nolan K, et al: Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychopharmacol 2004; 24:225—228
 
.
Scharre DW, Chang SI: Cognitive and behavioral effects of quetiapine in Alzheimer disease patients. Alzheimer Dis Assoc Disord 2002; 16:128—130
 
.
Walker C, Thomas J, Allen TS: Treating impulsivity, irritability, and aggression of antisocial personality disorder with quetiapine. Int J Offender Ther Comp Criminol 2003; 47:556—567
 
.
Yudofsky SC, Silver JM, Jackson W, et al: The overt aggression scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986; 143:35—39
 
.
Kreutzer J, Seel R, Marwitz J: Neurobehavioral Functioning Inventory. San Antonio, Harcourt Assessment, 1999
 
.
Randolph C: RBANS: Repeatable Battery for the Assessment of Neuropsychological Status. San Antonio, Harcourt Assessment, 1998
 
.
Sandel ME, Olive DA, Rader MA: Chlorpromazine-induced psychosis after brain injury. Brain Inj 1993; 7:77—83
 
.
Rao N, Jellinek HM, Woolston DC: Agitation in closed head injury: haloperidol effects on rehabilitation outcome. Arch Phys Med Rehabil 1985; 66:30—34
 
.
Stanislav SW: Cognitive effects of antipsychotic agents in persons with traumatic brain injury. Brain Inj 1997; 11:335—341
 
.
Corson AH, Barkenbus JE, Posey DJ, et al: A retrospective analysis of quetiapine in the treatment of pervasive developmental disorders. J Clin Psychiatry 2004; 65:1531—1536
 
.
Schreiber S, Klag E, Gross Y, et al: Beneficial effect of risperidone on sleep disturbance and psychosis following traumatic brain injury. Int Clin Psychopharmacol 1998; 13:273—275
 
.
Burke JG, Dursun SM, Reveley MA: Refractory symptomatic schizophrenia resulting from frontal lobe lesion: response to clozapine. J Psychiatry Neurosci 1999; 24:456—461
 
.
Temple MJ: Use of atypical anti-psychotics in the management of post-traumatic confusional states in traumatic brain injury. J R Army Med Corps 2003; 149:54—55
 
.
Krieger D, Hansen K, McDermott C, et al: Loxapine versus olanzapine in the treatment of delirium following traumatic brain injury. Neurorehabilitation 2003; 18:205—208
 
.
Bilder RM, Goldman RS, Volavka J, et al: Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry 2002; 159:1018—1028
 
.
Harvey PD, Meltzer H, Simpson GM, et al: Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia. Schizophr Res 2004; 66:101—113
 
.
Kivircik Akdede BB, Alptekin K, et al: Effects of quetiapine on cognitive functions in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:233—238
 
.
Eysenck MW: Anxiety and cognitive functioning: a multifaceted approach, in Perspectives of Cognitive Neurosciences. Edited by Lister RG, Weingartner HJ. New York, Oxford University Press, 1991
 
.
Massman PJ, Delis DC, Butters N, et al: The subcortical dysfunction hypothesis of memory deficits in depression: neuropsychological validation in a subgroup of patients. J Clin Exp Neuropsychol 1992; 14:687—706
 
.
Quemada JI, Munoz Cespedes JM, Ezkerra J, et al: Outcome of memory rehabilitation in traumatic brain injury assessed by neuropsychological tests and questionnaires. J Head Trauma Rehabil 2003; 18:532—540
 
.
Leahy BJ, Lam CS: Neuropsychological testing and functional outcome for individuals with traumatic brain injury. Brain Inj 1998; 12:1025—1035
 
+
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