Rematch in Developmental Disabilities, Printed in the USA. All rights reserved.
Vol. 13, pp. 381-392,
1992 Copyright
0891-4222E32 $5.00 + .oO Q 1992 Pergamon Press Ltd.
A Case of Phenobarbital Exacerbation of a Preexisting Maladaptive Behavior Partially Suppressed by Chlorpromazine and Misinterpreted as Chlorpromazine Efficacy Thomas E. Hanzel Faribault
Regional
Center
John E. Kalachnik Minnesota Department of Human Services
Stuart R. Harder Cambridge Regional Center
An adult female with developmenral disability was prescribed chlorpromazine for rhe target behaviors of aggression and self-injurious behavior (SIB), and she was prescribed phenobarbital for seizures. Upon a chlorpromazine minimal eflective dose reduction. target behaviors increased and dosage was returned to prior levels with the conclusion that chlorpromazine was controlling the target behaviors. Upon subsequent reduction and discontinuation of phenobarbital, however, chlorpromazine was able to be reduced with no increase in target behaviors. Ten years of behavioral data are presented to support the hypothesis that phenobarbital was exacerbating maladnptive behaviors. Given rardive dyskinesia (TD,). clinicians and interdisciplinary teams should remain alert lo the following client profile: (I) prescribed phenobarbital (or primidone). (2) prescribed neuroleptics, especially af high dosages, to control maladaptive behaviors, (3) failure of neurolepric gradual minimal effective dose attempts,
The authors would like to thank the following individuals for valuable advice and support: Sue Paquin, Human Services Technician Senior, Faribault Regional Center (FRC); Jeff Bauemfeind, Behavior Analyst, FRC; Shirley Jacobson, Human Services Technician Senior, FRC; Bill Saufferer, Administrator, FRC; Bill Combs, Unit Director, FRC; and Dave Campbell, Program Director, FRC. Requests for reprints should be sent to Thomas E. Hanzel, Faribault Regional Center, Faribault, MN 55021.
381
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T. E. Hanzel et al.
and (4) possible presence of behavioral procedures, especially intrusive procedures, to control maladaptive behaviors. This profile should trigger a “red flag” as to the possibility of phenobarbital behavioral side effects or exncerbation of preexisting makxiaptive behaviors.
Research has indicated that phenobarbital is associated with behavioral side effects (Camfield, Camfield, Smith, & Tibbles, 1985; Corbett, Trimble, & Nichol, 1985; Gay, 1984; Iivanainen & Savolainen, 1983; McGowan, Neville, & Reynolds, 1983; Vining, et al., 1987; Wolfe & Forsythe, 1978). Examples of such side effects that may occur at both toxic and therapeutic blood levels include aggression, frustration through verbal statements, hyperactivity, tantrums, irritability, and sleep disturbance (Collacott, Dignon, Hauck, & Ward, 1989; Wolfe & Forsythe, 1978). These behavioral side effects have been reported to occur for 42% of children (Wolfe & Forsythe, 1978) and 61% of the developmentally disabled (Gay, 1984). The use of neuroleptic as well as anticonvulsant medication is common with the developmentally disabled in both public (PRF) and community residential facilities (CRF) (Aman, Field, & Bridgman, 1985; Buck & Sprague, 1989; Hill, Balow, & Bruinicks, 1985; Intagliata & Rinck, 1985; Martin & Agran, 1985; Stone, Alvarez, Ellman, Horn, & White, 1989). While these studies do not provide information regarding concurrent neuroleptic and anticonvulsant use, the prevalence of combined psychotropic and anticonvulsant medication is reported to be approximately 20% for PRFs and 10% for CRFs (Briggs, 1989; Intagliata, & Rinck, 1985; Pulman, Pook, & Singh, 1979; White, 1983). Given that the use of phenobarbital appears to be lower in countries such as Australia, New Zealand, and Scotland (Fischbacher, 1987; Jonas, 1980; Pulman, et al., 1979), over 50% of anticonvulsant use (Briggs, 1989; Intagliata & Rinck, 1985) is comprised of phenobarbital, and about 80% of psychotropic use is comprised of neuroleptics (Hill et al., 1985). Therefore, it may be reasonably concluded that a number of individuals with developmental disability are prescribed both a neuroleptic and phenobarbital. Several authorities have questioned the overall approach taken with anticonvulsant side effects detection and monitoring. Gram, Bentsen, Parnas, and Flachs (1982), in a comprehensive review of 51 randomized doubleblind controlled studies, found that while the majority recorded side effects, data collection was unsystematic, and no quantifying rating scales were used. Cramer et al., (1983) report they reviewed the world literature and found that nearly all studies shared the common flaw of lack of standardized toxicity measurement. Finally, the common clinical procedure of tracking anticonvulsant side effects only via blood levels is called into question by Beardsley, Freeman, and Appel (1983), where availability of serum test results to physicians did not diminish patient reports of toxicity.
Phenobarbital Exacerbation
383
Given the above, the purpose of this report is to present a case of phenobarbital-induced behavioral disturbance using measures commonly found in the applied analysis of behavior. The case will illustrate how neuroleptic medication may be mistakenly continued in order to control behavioral side effects. METHOD
The client was a 38-year-old female residing in a Minnesota PRF, diagnosed with severe mental retardation. She had been institutionalized since the age of 8. At age 24, seizures were observed with a subsequent diagnosis of tonic-clonic type. Raw data from 1979 to 1989 was analyzed retrospectively as a function of pharmacological and programmatic interventions. This analysis was undertaken because of dramatic decreases in rates of aggression and selfinjurious behavior coinciding with a reduction in chlorpromazine despite historical failure to reduce this medication. The target behaviors of aggression and self-injurious behavior specifically included: (1) hand-biting, (2) hitting self with the fist, (3) throwing oneself against a wall or the floor, (4) forcefully running into other clients or staff, (5) hitting the head against objects or other people’s heads, and (6) hitting other people with the hand or fist. These target behaviors were identified by the Interdisciplinary Team and remained consistent in each annual Individual Treatment Plan. Incidence of target behaviors was measured using event recording. An incident reflected the occurrence of a target behavior, but not the actual number of times it was emitted during the occurrence since an intervention to terminate the behavior was invariably in place. Targets were recorded on a 24-hour basis across both residential and day program settings. Table 1 presents the pharmacological and programmatic interventions. Length of intervention was determined by a change in either the medication or behavior program in effect at or initiated after the start of the study. Interventions were determined by clinical considerations, such as doxepin for sleep disturbance or phenytoin to prevent seizure relapse upon phenobarbital discontinuation, regulatory committees, or the Individual Treatment Plan. The staff psychologist (TH) supervised behavior interventions, data collection, and staff training. Medications and behavior interventions involving the use of aversive procedures were reviewed by facility committees. Rate of the target behavior was determined by the number of incidents divided by the number of days per intervention. For ease of presentation, this mean daily rate was converted to mean monthly rate. Over the IO-year period there were 114 days for which data was unavailable due to events like hospitalizations.
%
525 550 550 550
15 10 19 10
21-Dee-82 21-Feb-83 9-Nov-83 18-Apr-84
29-Sep-82 22-Dee-82 22-Feb-83 IO-Now83
12 13 14 15
550
11
28-Sep-82
l-Aug-82
11
550
13
31-Jul-82
17-Sep-81
10
575 550 525 550 550 550
600
200 200 160 130
200
200
200 200
200 200 200 200 200 200 200
Chlorpromazine Phenobarbital
550 550
9 8 14 20 8 6 19
(mean/month)
Target Behavior Rate
0 0
Phenytoin
Medication (mg)
50 50 50 50
50
50
50 50
DRO, Mechanical Restraint, IM Inj.
50 50 50 50 50 50 50
Increase reinforcement density Decrease mechanical restraint to 15 min Add reinforcers Change mechanical restraint to physical holding Add tokens, response cost, and DRA D/C tokens, add variable cigarette reinforcement
Programs
Doxepin
TABLE 1 and Anticonvulsant, and Behavior Programs for Each Intervention
9 9
25Jul-81 16-Sep-81
I-Jun-81 26Jul-81
8 9
2 3 4 5 6 7
31&t-79 30-Nov-79 l-Jan-80 30-Jan-80 31-Jul-80 23-Mar-81 31-May-81
To
l-Jut-79 l-Nov-79 1-Dee-79 2-Jan-80 31-Jan-80 1-Aug-80 24Mar-8 1
From
1
Intervention
Date
Target Behavior Rate, Psychotropic
2 kl
8-May-84 26-Nov-84 26-Feb-85 3-Jun-85 30-Sep-85 l-Dee-85 l-Jul-86 2-Ott-86 4-Nov-86 I-Dee-86 5-Jan-87 17-Feb-87 16-Mar-87 21-Apr-87 20-A;g-87 17-Dee-87 21-Jan-88 21-Mar-88 21-Apr-88 13-Jul-88 5-Ott-88
5-Dee-88 2-Feb-89 13-Apr-89 7-Jui-89 30-Jun-89
19-Apr-84 9-Mav-84 27-N&34 27-Feb-85 4-Jun-85 I-Ott-85 2-Dee-85 2-Jul-86 3-act-86 5-Nov-86 2-Dee-86 6-Jan-87 18-Feb-87 17-Mar-87 22-Apr-87 21-Aug-87 18-Dee-87 22-Jan-88 22-Mar-88 22-Apr-88 14-J&88
6-Ott-88 6-Dee-88 3-Feb-89 14-Apr-89 8-Jun-89
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 38 39 40 41
0 0 2 0 0 0 1 4 2 2 2 0
3 1
325 300 300 275 250
550 550 550 550 550 550 525 525 525 525 525 525 525 525 500 475 450 425 400 375 350 0 100 130 150 150 130 loo 80 :; 25 0 0 0 0 0 0 0 0 0 0 0 0 0
8 0 0 0 0 0 0 0 0 0 0 0 0 0 0
8
100 100 100 60 30 0 0 0 0 0
: 0
0 0
8 0 0 0 0 0 0
8 0
50 25 0 0 0 0 0 0 0 0
D/C cigarette reinforcement
D/C physical holding and IM
Physical holding reduced to 15 min
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Phenobarbital blood levels were obtained from lab reports and clinical notations in the client’s medical record. Serum levels were obtained from blood samples drawn by nursing personnel and analyzed by facility laboratory technicians. Facility research committees reviewed and approved this case report. RESULTS Figure 1 presents the relationship between the dose of phenobarbital, the dose of chlorpromazine, and mean monthly target behavior rate for each intervention. Overall, the rate of target behaviors decreased as phenobarbital dose decreased and remained at low levels upon subsequent chlorpromazine reductions. Mean monthly rate of target behaviors after phenobarbital discontinuation (interventions 21 to 41) was 87 percent lower than when phenobarbital was 200 mg (interventions 1 to 13). The three highest target behavior rates at 200 milligrams of phenobarbital occurred at interventions 4, 7, and 12. A chlorpromazine reduction was involved in two interventions (4 and 12), whereas a decrease in mechanical restraint was involved in the remaining intervention (7). The increase at intervention 14, associated with a reduction in phenobarbital, was unaccounted for and may have been due to withdrawal effects. The only reason phenobarbital reductions continued despite this increase was that a more detailed monthly analysis for this time period showed a decreasing trend relative to the beginning of the condition. Table 2 presents the total target behavior incidents exhibited within a 3 lday period coinciding with each of the 13 phenobarbital blood level dates found in the medical record. The 31 days included the 15 days prior to and the 15 days after the blood level date. Because a phenobarbital dosage change anytime 35 days before or 14 days after a blood level date could affect the data due to the requirement of 21 days for steady state blood levels to be achieved (Garnett, 1989) the data collection period was shifted slightly forward or back if such an event occurred. Two of the 13 blood levels exceeded the recommended therapeutic range of 15 to 40 pg/ml (Brown, 1978; Garnet& 1989). The total target behaviors exhibited during the two blood levels exceeding 40 pg/ml were lower than or near those exhibited when other blood levels at the same dose were within the therapeutic range.
DISCUSSION The data presented show that the target behaviors of aggression and selfinjury thought to be treated and partially suppressed with chlorpromazine were, in reality, behavioral side effects of phenobarbital.
Phenobarbital Exacerbation
Phenobarbital
Conseculive
Dose
Treatment
FIGURE 1. The effects of phenobarbital aggression and self-injurious behavior.
387
(mglday)
lnlerventions
and chlorpromazine
on the average monthly rate of
The major implication of this case is that clinicians and interdisciplinary teams (IDTs) working with individuals with developmental disabilities (DD) must be cognizant of the possibility of phenobarbital behavior side effects or exacerbation of preexisting maladaptive behaviors. There are two reasons for this. First, unnecessary behavioral interventions may be used TABLE 2 31-Day Target Behavior Level as a Function of Phenobarbital Blood Levels Date of Blood Level (Intervention During Which Taken) 12-24-79 5-11-81 5-19-82 2-16-83 3-16-83 5-2-83 5-24-83 4-20-84 5-16-84 2-27-85 3-14-85 6-25-85 9-25-85
(3) (7) (10) (13) (14) (14) (14) (16) (17) (19) (19) (20) (20)
Phenobarbital Blood Level olp/JN 33 22 50 43 24 25 20 25 15 22 18 5 4
Total Target Phenobarbital Dose (mg) 200 200 200 200 160 160 160 100 100 60 60
Behaviors for 3 1-Day Period 14 23 17 15 21 10 21 18 0 10 6 3 0
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mistakenly to manage increased maladaptive behaviors. These interventions may include inappropriate aversive procedures especially in light of more serious maladaptive behaviors, such as SIB and aggression. These procedures were terminated here following phenobarbital discontinuation. Second, unnecessary psychotropic medication or increased psychotropic medication dosages may be used mistakenly to manage increased maladaptive behaviors. This situation is especially relevant for neuroleptics where aggression and SIB are the two main behavioral problems predicting neuroleptic use (Stone et al., 1989). The inappropriate use of neuroleptics is of critical concern because these medications are associated with tardive dyskinesia (TD) (American Psychiatric Association, 1979), and cumulative neuroleptic dose has been reported to be associated with more severe forms of TD (Gualtieri, Schroeder, Hicks, & Quade, 1986). In this case, persistent TD was diagnosed. Questions have been raised regarding the effectiveness of higher neuroleptic dosages with developmentally disabled individuals to control maladaptive target behaviors (Lipman, 1982). In regard to chlorpromazine, little effectiveness above 500 mg per day is indicated for developmentally disabled individuals (Cord Laboratories, 1989). Therefore, the clinician and IDT should be alert to the following client profile: (1) prescribed phenobarbital (or primidone, which is also used for seizures and is metabolized to phenobarbital); (2) prescribed neuroleptics, especially at high dosages, to control maladaptive behaviors; (3) failure of gradual minimal effective dose reductions; and (4) the possible presence of behavioral procedures, especially intrusive procedures, to control maladaptive behaviors. Given the presence of this profile, an automatic “red flag” should be raised as to the possibility of phenobarbital behavioral side effects or exacerbation of preexisting maladaptive behaviors. Phenobarbital behavioral side effects are generally considered to be frustration, temper tantrums, irritability, sleep disturbance, hyperactivity, aggression, and noncompliance (Gadow, 1986; Gay, 1984; Wolf & Forsythe, 1978; Vining et al., 1987). Although preexisting SIB has been reported to increase as a function of the related barbiturate secobarbital (Barron & Sandman, 1983), SIB itself has not been listed as a behavioral side effect of phenobarbital. Since phenobarbital may act by impairing inhibitory control and since this may occur more so in susceptible individuals, such as the developmentally disabled (Gay, 1984), the possibility of SIB as a behavioral side effect for these individuals should be considered and explored further. There are several limitations to this report. The first is that this is a retrospective case analysis. The second is the lack of formal reliability checks. The third is the possibility that chlorpromazine induced the seizures for
Phenobarbital Exacerbation
389
which phenobarbital was subsequently prescribed. Remick and Fine (1979) note that chlorpromazine is the most commonly implicated neuroleptic for this. Such a possibility, however, does not effect the implications of the case because: (1) phenobarbital is implicated in the exacerbation of preexisting behavioral problems (Wolfe & Forsythe 1978), and (2) high rates of target behaviors were, nonetheless, associated with phenobarbital and the failure of chlorpromazine reduction attempts. The fourth is the possibility that behavioral side effects were truly a function of higher or toxic phenobarbital serum blood levels despite the serum blood level data presented and the view that while neurological side effects are seen with high serum concentrations, other side effects, including behavioral problems, are unrelated to serum concentrations (Choonara & Rane, 1990). The fifth is the possibility of a mistaken association between phenobarbital and exacerbated maladaptive behavior because phenobarbital lowered chlorpromazine blood levels below therapeutic effectiveness (Sovner & DesNoyers Hurley, 1982; Kutt, 1984). This is negated by the extensive chlorpromazine reduction possible once phenobarbital was discontinued. Conversely, chlorpromazine serum levels lowered by phenobarbital may have become so excessively therapeutic once phenobarbital was discontinued that subsequent chlorpromazine dosage reductions were possible because chlorpromazine levels remained within, albeit at the lower end, the therapeutic range. There is question, however, as to (1) whether phenobarbital has such effects on thioridazine and chlorpromazine as compared to haloperidol and mesioridazine, which may have a different mechanism of transformation (Linnoila, Viukari, Vaisanen, & Auvinen, 1980), and (2) the extent of such an effect on actual clinical data and behavior (Kutt, 1984). The sixth is similar and regards doxepin since phenobarbital may reduce tricyclic antidepressant blood levels (McEvoy, 1989; Sovner & DesNoyers, 1982). Doxepin was reduced at interventions 17 and 18, while, prior to this, phenobarbital was reduced from 130 mg to 100 mg at intervention 16, which, in turn, only consisted of approximately 3 weeks. It is possible that doxepin, despite being prescribed for sleep disturbance, was in actuality controlling the target behaviors because serum blood levels increased once the phenobarbital was decreased by a large enough amount. This possibility, however, is negated for two reasons. First, target behavior rates remained low following doxepin discontinuation. If doxepin was the controlling variable, rates should have increased. Second, the extent of such an effect on actual clinical data and behavior is unclear (Kutt, 1984; McEvoy. 1989). In summary, this case further strengthens the need for service providers to become aware of the possibility that not only the use of psychotropic medications but also some anticonvulsant medications can be potential variables that may be serving to exacerbate an individual’s maladaptive
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behavior. Unless this is recognized and strategies are undertaken to assess and correct this variable, it is feared that some individuals will continue to receive additional medication and/or unnecessary behavioral interventions for dealing with their maladaptive behavior. Given the possibility of TD from neuroleptics and the possibility of intrusive and restrictive procedures, this fear is of public health importance for individuals with developmental disabilities in light of a growing literature regarding unnecessary anticonvulsant polypharmacy and possible withdrawal of anticonvulsants in individuals who meet specific entry criteria, such as being seizure-free for at least 2 years (Albright & Bruni, 1985; Alvarez, 1989; Callaghan, Garrett, & Goggin, 1988; Schmidt, 1983; Shinnar et al., 1985; Shorvon & Reynolds, 1977). REFERENCES Albright, P., & Bruni, J. (1985). Reduction of polypharmacy in epileptic patients. Archives of Neurology, 42,797-799. Alvarez, N. (1989). Discontinuation of antiepileptic medications in patients with developmental disability and diagnosis of epilepsy. American Journal on Mental Retardation, 93,593-599. Aman, M. G., Field, C. J., & Bridgman, G. D. (1985). City-wide survey of drug patterns among noninstitutionalized mentally retarded persons. Applied Research in Mental Retardation, 6, 159-171. American Psychiatric Association (1979). Tardive dyskinesia. Task force report 18. Washington: American Psychiatric Association Press. Barron, J., & Sandman, C. A. (1983). Relationship of sedative-hypnotic response to self-injurious behavior and stereotypy by mentally retarded clients. American Journal of Mental Deficiency, 90,124-129. Beardsley, R. S., Freeman, J. M., & Appel, F. A. (1983). Anticonvulsant serum levels are useful only if the physician appropriately uses them: An assessment of the impact of providing serum level data to physicians. Epilepsia, 24, 330-335. Briggs, R. (1989). Monitoring and evaluating psychotropic drug use for persons with mental retardation: A follow-up report. American Journal on Mental Retardation, 93,633-639. Brown, T. R. (1978). Drug therapy reviews: Clinical pharmacology of antiepileptic drugs. American Journal of Hospital Pharmacy, 35, 1048-1056. Buck, J. A., & Sprague, R. L. (1989). Psychotropic medication of mentally retarded residents in community long-term care facilities. American Journal of Mental Deficiency, 93.618-623. Callaghan, N., Garrett, A., & Goggin, T. (1988). Withdrawal of anticonvulsant drugs in patients free of seizures for two years. New England Journal of Medicine, 318,942-946. Camfield, P R., Camtield, C. S., Smith, E. C., & Tibbles, J. A. R. (1985). Newly treated childhood epilepsy: A prospective study of recurrences and side effects. Neurology, 35.722-725. Choonara, 1. A., & Rane, A. (1990). Therapeutic drug monitoring of anticonvulsants. State of the art. Clinical Pharmacokinetics, 18, 318-328. CoIlacott, R. A., Dignon, A., Hauck, A., & Ward, J. W. (1989). Clinical and therapeutic monitoring of epilepsy in a mental handicap unit. British Journal of Psychiatry, X5,522-525. Corbett, J. A., Trimble, M. R., & Nichol, T. C. (1985). Behavioral and cognitive impairments in children with epilepsy: The long-term effects of anticonvulsant therapy. Journal of the American Academy of Child Psychiatry, 24.17-23. Cord Laboratories, Inc. (1989). Package insert for chlorpromazine hydrochloride syrup, USP oral solution (concentrate) tablets, USP. (7020, C89/3). Broomfield, CO: Author.
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Exacerbation
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Cramer, J. A., Smith, D., Mattson, R. H., De&ado Escueta, A. V., Collins, J. F., & the VA Epilepsy Cooperative Study Group (1983). A method of quantification for the evaluation of antiepileptic drug therapy. Neurology, 33 (Suppl.), 26-37. Fischbacher, E. (1987). Prescribing in a hospital for the mentally retarded. Journal of Mental Deficiency Research, 31.17-29. Gadow, K. D. (1986). Children on medication (Vol. 2). Epilepsy, emotional disturbance, and a&rlescent disorders. San Diego: College-Hill. Garnett, W. R. (1989). Epilepsy. In J. T. DiPiro, R. L. Tabert, B. E. Hayes, G. C. Yees, & L. M. Posey (Eds.), Pharmacotherapy: A pathophysiologic approach (pp. 611-631). New York: Elsevier. Gay, P. E. (1984). Effects of antiepileptic drugs and seizure type on operant responding in mentally retarded persons. Epilepsia, 25, 377-386. Gram, L., Bentsen. K. D., Parnas, J., & FIachs, H. (1982). Controlled trials in epilepsy: A review. Epilepsia, 23.491-519.
Gualtieri, C. T., Schroeder, S. R., Hicks, R. E., & Quade, D. (1986). Tardive dyskinesia in young mentally retarded individuals. Archives of General Psychiatry 43, 335-340. Hill, B. K., Balow, E. A., & Bruininks, R. H. (1985). A national study of prescribed drugs in institutions and community residential facilities for mentally retarded people. Psychopharmacology Bulletin, 21, 279-284.
Iivanainen, M., & Savolainen, H. (1983). Side effects of phenobarbital and phenytoin during longterm treatment of epilepsy. Acta Neurologica Scandinavica, 68 (SuppI.), 49-67. Intagliata, J., & Rinck, C. (1985). Psychoactive drug use in public and community residential facilities for mentally retarded persons. Psychopharmacology Bulletin, 21,268-278. Jonas, 0. (1980). Pattern of drug prescribing in a residential centre for the intellectually handicapped. Australian Journal of Developmental Disabilities, 6,25-29. Kutt, H. (1984). Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia, 25 (Suppl.), 118-131. Linnoila, M., Viukari, M., Vaisanen, K., & Auvinen, J. (1980). Effect of anticonvulsants on plasma haloperidol and thioridazine levels. American Journal of Psychiatry, 137, 819-821. Lipman, R. S. (1982). Psychotropic drugs in mental retardation: The known and the unknown. In K. D. Gadow & I. Bialer (Eds.), Advances in learning and behavioral disabilities (Vol. 1, pp. 261-282). Greenwich, CT JAI Press. Martin, J. E., & Agran, M. (1985). Psychotropic and anticonvulsant drug use by mentally retarded adults across community residential and vocational placements. Applied Research in Mental Retardation, 6, 33-49.
McEvoy, G. K. (Ed.) (1989). American hospital formulary service. Bethesda, MD: American Society of Hospital Pharmacists. McGowan, M., NeviIle, B. G. R., & Reynolds, E. H. (1983). Comparative monotherapy in children with epilepsy. British Journal of Clinical Practice, 27 (Suppl.), 115-118. Pulman, R. M., Pook, R. B., & Singh, N. N. (1979). Prevalence of drug therapy for institutionalized mentally retarded children. Australian Journal of Mental Retardation, 5,212-214. Remick, R. A., & Fine, S. H. (1979). Antipsychotic drugs and seizures. Journal of Clinical Psychiatry, 40, 78-80.
Schmidt, D. (1983). Reduction of two-drug therapy in intractable epilepsy. Epilepsia, 24, 368-376.
Shinnar, S., Vining, E. P. G., Mellits, E. D., D’Souza, B. J., Holden, K., Baumgardner, B. A. (1985). Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. New England Journal of Medicine, 313,976980. Shorvon, S. D., & Reynolds, E. H. (1977). Unnecessary polypharmacy for epilepsy. British Medical Journal, 1, 1635-1637. Sovner, R., & DesNoyers Hurley, A. (E&s.) (1982). Psychotropic drug interactions with anticonvulsants. Psychiatric Aspects of Mental Retardation Newsletter; 1, 17-23.
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Stone, R. K., Alvarez, W. F., Ellman, G., Horn, A. C., & White, J. F. (1989). Prevalence and prediction of psychotropic drug use in California developmental centers. American Journal on Mental Retardation, 93,627-632.
Vming, E. P. G., Mellits, E. D., Dorsen. M. M., Cataldo, M. F., Quaskey, S. A., Spielberg, S. P (1987). Psychological and behavioral effects of antiepileptic drugs in children: A double-blind comparison between phenobarbital and valproic acid. Pediatrics, 80, 165174. White, A. J. R. (1983). Changing patterns of psychotropic drug use with the mentally retarded. New Zealand Medical Journal, 96,686-688. Wolfe, S. M., & Forsythe, A. (1978). Behavior disturbance, phenobarbital, and febrile seizures. Pedintrics, 61,728-731.
Vol. 13, pp. 381-392,
1992 Copyright
0891-4222E32 $5.00 + .oO Q 1992 Pergamon Press Ltd.
A Case of Phenobarbital Exacerbation of a Preexisting Maladaptive Behavior Partially Suppressed by Chlorpromazine and Misinterpreted as Chlorpromazine Efficacy Thomas E. Hanzel Faribault
Regional
Center
John E. Kalachnik Minnesota Department of Human Services
Stuart R. Harder Cambridge Regional Center
An adult female with developmenral disability was prescribed chlorpromazine for rhe target behaviors of aggression and self-injurious behavior (SIB), and she was prescribed phenobarbital for seizures. Upon a chlorpromazine minimal eflective dose reduction. target behaviors increased and dosage was returned to prior levels with the conclusion that chlorpromazine was controlling the target behaviors. Upon subsequent reduction and discontinuation of phenobarbital, however, chlorpromazine was able to be reduced with no increase in target behaviors. Ten years of behavioral data are presented to support the hypothesis that phenobarbital was exacerbating maladnptive behaviors. Given rardive dyskinesia (TD,). clinicians and interdisciplinary teams should remain alert lo the following client profile: (I) prescribed phenobarbital (or primidone). (2) prescribed neuroleptics, especially af high dosages, to control maladaptive behaviors, (3) failure of neurolepric gradual minimal effective dose attempts,
The authors would like to thank the following individuals for valuable advice and support: Sue Paquin, Human Services Technician Senior, Faribault Regional Center (FRC); Jeff Bauemfeind, Behavior Analyst, FRC; Shirley Jacobson, Human Services Technician Senior, FRC; Bill Saufferer, Administrator, FRC; Bill Combs, Unit Director, FRC; and Dave Campbell, Program Director, FRC. Requests for reprints should be sent to Thomas E. Hanzel, Faribault Regional Center, Faribault, MN 55021.
381
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and (4) possible presence of behavioral procedures, especially intrusive procedures, to control maladaptive behaviors. This profile should trigger a “red flag” as to the possibility of phenobarbital behavioral side effects or exncerbation of preexisting makxiaptive behaviors.
Research has indicated that phenobarbital is associated with behavioral side effects (Camfield, Camfield, Smith, & Tibbles, 1985; Corbett, Trimble, & Nichol, 1985; Gay, 1984; Iivanainen & Savolainen, 1983; McGowan, Neville, & Reynolds, 1983; Vining, et al., 1987; Wolfe & Forsythe, 1978). Examples of such side effects that may occur at both toxic and therapeutic blood levels include aggression, frustration through verbal statements, hyperactivity, tantrums, irritability, and sleep disturbance (Collacott, Dignon, Hauck, & Ward, 1989; Wolfe & Forsythe, 1978). These behavioral side effects have been reported to occur for 42% of children (Wolfe & Forsythe, 1978) and 61% of the developmentally disabled (Gay, 1984). The use of neuroleptic as well as anticonvulsant medication is common with the developmentally disabled in both public (PRF) and community residential facilities (CRF) (Aman, Field, & Bridgman, 1985; Buck & Sprague, 1989; Hill, Balow, & Bruinicks, 1985; Intagliata & Rinck, 1985; Martin & Agran, 1985; Stone, Alvarez, Ellman, Horn, & White, 1989). While these studies do not provide information regarding concurrent neuroleptic and anticonvulsant use, the prevalence of combined psychotropic and anticonvulsant medication is reported to be approximately 20% for PRFs and 10% for CRFs (Briggs, 1989; Intagliata, & Rinck, 1985; Pulman, Pook, & Singh, 1979; White, 1983). Given that the use of phenobarbital appears to be lower in countries such as Australia, New Zealand, and Scotland (Fischbacher, 1987; Jonas, 1980; Pulman, et al., 1979), over 50% of anticonvulsant use (Briggs, 1989; Intagliata & Rinck, 1985) is comprised of phenobarbital, and about 80% of psychotropic use is comprised of neuroleptics (Hill et al., 1985). Therefore, it may be reasonably concluded that a number of individuals with developmental disability are prescribed both a neuroleptic and phenobarbital. Several authorities have questioned the overall approach taken with anticonvulsant side effects detection and monitoring. Gram, Bentsen, Parnas, and Flachs (1982), in a comprehensive review of 51 randomized doubleblind controlled studies, found that while the majority recorded side effects, data collection was unsystematic, and no quantifying rating scales were used. Cramer et al., (1983) report they reviewed the world literature and found that nearly all studies shared the common flaw of lack of standardized toxicity measurement. Finally, the common clinical procedure of tracking anticonvulsant side effects only via blood levels is called into question by Beardsley, Freeman, and Appel (1983), where availability of serum test results to physicians did not diminish patient reports of toxicity.
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Given the above, the purpose of this report is to present a case of phenobarbital-induced behavioral disturbance using measures commonly found in the applied analysis of behavior. The case will illustrate how neuroleptic medication may be mistakenly continued in order to control behavioral side effects. METHOD
The client was a 38-year-old female residing in a Minnesota PRF, diagnosed with severe mental retardation. She had been institutionalized since the age of 8. At age 24, seizures were observed with a subsequent diagnosis of tonic-clonic type. Raw data from 1979 to 1989 was analyzed retrospectively as a function of pharmacological and programmatic interventions. This analysis was undertaken because of dramatic decreases in rates of aggression and selfinjurious behavior coinciding with a reduction in chlorpromazine despite historical failure to reduce this medication. The target behaviors of aggression and self-injurious behavior specifically included: (1) hand-biting, (2) hitting self with the fist, (3) throwing oneself against a wall or the floor, (4) forcefully running into other clients or staff, (5) hitting the head against objects or other people’s heads, and (6) hitting other people with the hand or fist. These target behaviors were identified by the Interdisciplinary Team and remained consistent in each annual Individual Treatment Plan. Incidence of target behaviors was measured using event recording. An incident reflected the occurrence of a target behavior, but not the actual number of times it was emitted during the occurrence since an intervention to terminate the behavior was invariably in place. Targets were recorded on a 24-hour basis across both residential and day program settings. Table 1 presents the pharmacological and programmatic interventions. Length of intervention was determined by a change in either the medication or behavior program in effect at or initiated after the start of the study. Interventions were determined by clinical considerations, such as doxepin for sleep disturbance or phenytoin to prevent seizure relapse upon phenobarbital discontinuation, regulatory committees, or the Individual Treatment Plan. The staff psychologist (TH) supervised behavior interventions, data collection, and staff training. Medications and behavior interventions involving the use of aversive procedures were reviewed by facility committees. Rate of the target behavior was determined by the number of incidents divided by the number of days per intervention. For ease of presentation, this mean daily rate was converted to mean monthly rate. Over the IO-year period there were 114 days for which data was unavailable due to events like hospitalizations.
%
525 550 550 550
15 10 19 10
21-Dee-82 21-Feb-83 9-Nov-83 18-Apr-84
29-Sep-82 22-Dee-82 22-Feb-83 IO-Now83
12 13 14 15
550
11
28-Sep-82
l-Aug-82
11
550
13
31-Jul-82
17-Sep-81
10
575 550 525 550 550 550
600
200 200 160 130
200
200
200 200
200 200 200 200 200 200 200
Chlorpromazine Phenobarbital
550 550
9 8 14 20 8 6 19
(mean/month)
Target Behavior Rate
0 0
Phenytoin
Medication (mg)
50 50 50 50
50
50
50 50
DRO, Mechanical Restraint, IM Inj.
50 50 50 50 50 50 50
Increase reinforcement density Decrease mechanical restraint to 15 min Add reinforcers Change mechanical restraint to physical holding Add tokens, response cost, and DRA D/C tokens, add variable cigarette reinforcement
Programs
Doxepin
TABLE 1 and Anticonvulsant, and Behavior Programs for Each Intervention
9 9
25Jul-81 16-Sep-81
I-Jun-81 26Jul-81
8 9
2 3 4 5 6 7
31&t-79 30-Nov-79 l-Jan-80 30-Jan-80 31-Jul-80 23-Mar-81 31-May-81
To
l-Jut-79 l-Nov-79 1-Dee-79 2-Jan-80 31-Jan-80 1-Aug-80 24Mar-8 1
From
1
Intervention
Date
Target Behavior Rate, Psychotropic
2 kl
8-May-84 26-Nov-84 26-Feb-85 3-Jun-85 30-Sep-85 l-Dee-85 l-Jul-86 2-Ott-86 4-Nov-86 I-Dee-86 5-Jan-87 17-Feb-87 16-Mar-87 21-Apr-87 20-A;g-87 17-Dee-87 21-Jan-88 21-Mar-88 21-Apr-88 13-Jul-88 5-Ott-88
5-Dee-88 2-Feb-89 13-Apr-89 7-Jui-89 30-Jun-89
19-Apr-84 9-Mav-84 27-N&34 27-Feb-85 4-Jun-85 I-Ott-85 2-Dee-85 2-Jul-86 3-act-86 5-Nov-86 2-Dee-86 6-Jan-87 18-Feb-87 17-Mar-87 22-Apr-87 21-Aug-87 18-Dee-87 22-Jan-88 22-Mar-88 22-Apr-88 14-J&88
6-Ott-88 6-Dee-88 3-Feb-89 14-Apr-89 8-Jun-89
16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 38 39 40 41
0 0 2 0 0 0 1 4 2 2 2 0
3 1
325 300 300 275 250
550 550 550 550 550 550 525 525 525 525 525 525 525 525 500 475 450 425 400 375 350 0 100 130 150 150 130 loo 80 :; 25 0 0 0 0 0 0 0 0 0 0 0 0 0
8 0 0 0 0 0 0 0 0 0 0 0 0 0 0
8
100 100 100 60 30 0 0 0 0 0
: 0
0 0
8 0 0 0 0 0 0
8 0
50 25 0 0 0 0 0 0 0 0
D/C cigarette reinforcement
D/C physical holding and IM
Physical holding reduced to 15 min
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Phenobarbital blood levels were obtained from lab reports and clinical notations in the client’s medical record. Serum levels were obtained from blood samples drawn by nursing personnel and analyzed by facility laboratory technicians. Facility research committees reviewed and approved this case report. RESULTS Figure 1 presents the relationship between the dose of phenobarbital, the dose of chlorpromazine, and mean monthly target behavior rate for each intervention. Overall, the rate of target behaviors decreased as phenobarbital dose decreased and remained at low levels upon subsequent chlorpromazine reductions. Mean monthly rate of target behaviors after phenobarbital discontinuation (interventions 21 to 41) was 87 percent lower than when phenobarbital was 200 mg (interventions 1 to 13). The three highest target behavior rates at 200 milligrams of phenobarbital occurred at interventions 4, 7, and 12. A chlorpromazine reduction was involved in two interventions (4 and 12), whereas a decrease in mechanical restraint was involved in the remaining intervention (7). The increase at intervention 14, associated with a reduction in phenobarbital, was unaccounted for and may have been due to withdrawal effects. The only reason phenobarbital reductions continued despite this increase was that a more detailed monthly analysis for this time period showed a decreasing trend relative to the beginning of the condition. Table 2 presents the total target behavior incidents exhibited within a 3 lday period coinciding with each of the 13 phenobarbital blood level dates found in the medical record. The 31 days included the 15 days prior to and the 15 days after the blood level date. Because a phenobarbital dosage change anytime 35 days before or 14 days after a blood level date could affect the data due to the requirement of 21 days for steady state blood levels to be achieved (Garnett, 1989) the data collection period was shifted slightly forward or back if such an event occurred. Two of the 13 blood levels exceeded the recommended therapeutic range of 15 to 40 pg/ml (Brown, 1978; Garnet& 1989). The total target behaviors exhibited during the two blood levels exceeding 40 pg/ml were lower than or near those exhibited when other blood levels at the same dose were within the therapeutic range.
DISCUSSION The data presented show that the target behaviors of aggression and selfinjury thought to be treated and partially suppressed with chlorpromazine were, in reality, behavioral side effects of phenobarbital.
Phenobarbital Exacerbation
Phenobarbital
Conseculive
Dose
Treatment
FIGURE 1. The effects of phenobarbital aggression and self-injurious behavior.
387
(mglday)
lnlerventions
and chlorpromazine
on the average monthly rate of
The major implication of this case is that clinicians and interdisciplinary teams (IDTs) working with individuals with developmental disabilities (DD) must be cognizant of the possibility of phenobarbital behavior side effects or exacerbation of preexisting maladaptive behaviors. There are two reasons for this. First, unnecessary behavioral interventions may be used TABLE 2 31-Day Target Behavior Level as a Function of Phenobarbital Blood Levels Date of Blood Level (Intervention During Which Taken) 12-24-79 5-11-81 5-19-82 2-16-83 3-16-83 5-2-83 5-24-83 4-20-84 5-16-84 2-27-85 3-14-85 6-25-85 9-25-85
(3) (7) (10) (13) (14) (14) (14) (16) (17) (19) (19) (20) (20)
Phenobarbital Blood Level olp/JN 33 22 50 43 24 25 20 25 15 22 18 5 4
Total Target Phenobarbital Dose (mg) 200 200 200 200 160 160 160 100 100 60 60
Behaviors for 3 1-Day Period 14 23 17 15 21 10 21 18 0 10 6 3 0
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mistakenly to manage increased maladaptive behaviors. These interventions may include inappropriate aversive procedures especially in light of more serious maladaptive behaviors, such as SIB and aggression. These procedures were terminated here following phenobarbital discontinuation. Second, unnecessary psychotropic medication or increased psychotropic medication dosages may be used mistakenly to manage increased maladaptive behaviors. This situation is especially relevant for neuroleptics where aggression and SIB are the two main behavioral problems predicting neuroleptic use (Stone et al., 1989). The inappropriate use of neuroleptics is of critical concern because these medications are associated with tardive dyskinesia (TD) (American Psychiatric Association, 1979), and cumulative neuroleptic dose has been reported to be associated with more severe forms of TD (Gualtieri, Schroeder, Hicks, & Quade, 1986). In this case, persistent TD was diagnosed. Questions have been raised regarding the effectiveness of higher neuroleptic dosages with developmentally disabled individuals to control maladaptive target behaviors (Lipman, 1982). In regard to chlorpromazine, little effectiveness above 500 mg per day is indicated for developmentally disabled individuals (Cord Laboratories, 1989). Therefore, the clinician and IDT should be alert to the following client profile: (1) prescribed phenobarbital (or primidone, which is also used for seizures and is metabolized to phenobarbital); (2) prescribed neuroleptics, especially at high dosages, to control maladaptive behaviors; (3) failure of gradual minimal effective dose reductions; and (4) the possible presence of behavioral procedures, especially intrusive procedures, to control maladaptive behaviors. Given the presence of this profile, an automatic “red flag” should be raised as to the possibility of phenobarbital behavioral side effects or exacerbation of preexisting maladaptive behaviors. Phenobarbital behavioral side effects are generally considered to be frustration, temper tantrums, irritability, sleep disturbance, hyperactivity, aggression, and noncompliance (Gadow, 1986; Gay, 1984; Wolf & Forsythe, 1978; Vining et al., 1987). Although preexisting SIB has been reported to increase as a function of the related barbiturate secobarbital (Barron & Sandman, 1983), SIB itself has not been listed as a behavioral side effect of phenobarbital. Since phenobarbital may act by impairing inhibitory control and since this may occur more so in susceptible individuals, such as the developmentally disabled (Gay, 1984), the possibility of SIB as a behavioral side effect for these individuals should be considered and explored further. There are several limitations to this report. The first is that this is a retrospective case analysis. The second is the lack of formal reliability checks. The third is the possibility that chlorpromazine induced the seizures for
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which phenobarbital was subsequently prescribed. Remick and Fine (1979) note that chlorpromazine is the most commonly implicated neuroleptic for this. Such a possibility, however, does not effect the implications of the case because: (1) phenobarbital is implicated in the exacerbation of preexisting behavioral problems (Wolfe & Forsythe 1978), and (2) high rates of target behaviors were, nonetheless, associated with phenobarbital and the failure of chlorpromazine reduction attempts. The fourth is the possibility that behavioral side effects were truly a function of higher or toxic phenobarbital serum blood levels despite the serum blood level data presented and the view that while neurological side effects are seen with high serum concentrations, other side effects, including behavioral problems, are unrelated to serum concentrations (Choonara & Rane, 1990). The fifth is the possibility of a mistaken association between phenobarbital and exacerbated maladaptive behavior because phenobarbital lowered chlorpromazine blood levels below therapeutic effectiveness (Sovner & DesNoyers Hurley, 1982; Kutt, 1984). This is negated by the extensive chlorpromazine reduction possible once phenobarbital was discontinued. Conversely, chlorpromazine serum levels lowered by phenobarbital may have become so excessively therapeutic once phenobarbital was discontinued that subsequent chlorpromazine dosage reductions were possible because chlorpromazine levels remained within, albeit at the lower end, the therapeutic range. There is question, however, as to (1) whether phenobarbital has such effects on thioridazine and chlorpromazine as compared to haloperidol and mesioridazine, which may have a different mechanism of transformation (Linnoila, Viukari, Vaisanen, & Auvinen, 1980), and (2) the extent of such an effect on actual clinical data and behavior (Kutt, 1984). The sixth is similar and regards doxepin since phenobarbital may reduce tricyclic antidepressant blood levels (McEvoy, 1989; Sovner & DesNoyers, 1982). Doxepin was reduced at interventions 17 and 18, while, prior to this, phenobarbital was reduced from 130 mg to 100 mg at intervention 16, which, in turn, only consisted of approximately 3 weeks. It is possible that doxepin, despite being prescribed for sleep disturbance, was in actuality controlling the target behaviors because serum blood levels increased once the phenobarbital was decreased by a large enough amount. This possibility, however, is negated for two reasons. First, target behavior rates remained low following doxepin discontinuation. If doxepin was the controlling variable, rates should have increased. Second, the extent of such an effect on actual clinical data and behavior is unclear (Kutt, 1984; McEvoy. 1989). In summary, this case further strengthens the need for service providers to become aware of the possibility that not only the use of psychotropic medications but also some anticonvulsant medications can be potential variables that may be serving to exacerbate an individual’s maladaptive
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behavior. Unless this is recognized and strategies are undertaken to assess and correct this variable, it is feared that some individuals will continue to receive additional medication and/or unnecessary behavioral interventions for dealing with their maladaptive behavior. Given the possibility of TD from neuroleptics and the possibility of intrusive and restrictive procedures, this fear is of public health importance for individuals with developmental disabilities in light of a growing literature regarding unnecessary anticonvulsant polypharmacy and possible withdrawal of anticonvulsants in individuals who meet specific entry criteria, such as being seizure-free for at least 2 years (Albright & Bruni, 1985; Alvarez, 1989; Callaghan, Garrett, & Goggin, 1988; Schmidt, 1983; Shinnar et al., 1985; Shorvon & Reynolds, 1977). REFERENCES Albright, P., & Bruni, J. (1985). Reduction of polypharmacy in epileptic patients. Archives of Neurology, 42,797-799. Alvarez, N. (1989). Discontinuation of antiepileptic medications in patients with developmental disability and diagnosis of epilepsy. American Journal on Mental Retardation, 93,593-599. Aman, M. G., Field, C. J., & Bridgman, G. D. (1985). City-wide survey of drug patterns among noninstitutionalized mentally retarded persons. Applied Research in Mental Retardation, 6, 159-171. American Psychiatric Association (1979). Tardive dyskinesia. Task force report 18. Washington: American Psychiatric Association Press. Barron, J., & Sandman, C. A. (1983). Relationship of sedative-hypnotic response to self-injurious behavior and stereotypy by mentally retarded clients. American Journal of Mental Deficiency, 90,124-129. Beardsley, R. S., Freeman, J. M., & Appel, F. A. (1983). Anticonvulsant serum levels are useful only if the physician appropriately uses them: An assessment of the impact of providing serum level data to physicians. Epilepsia, 24, 330-335. Briggs, R. (1989). Monitoring and evaluating psychotropic drug use for persons with mental retardation: A follow-up report. American Journal on Mental Retardation, 93,633-639. Brown, T. R. (1978). Drug therapy reviews: Clinical pharmacology of antiepileptic drugs. American Journal of Hospital Pharmacy, 35, 1048-1056. Buck, J. A., & Sprague, R. L. (1989). Psychotropic medication of mentally retarded residents in community long-term care facilities. American Journal of Mental Deficiency, 93.618-623. Callaghan, N., Garrett, A., & Goggin, T. (1988). Withdrawal of anticonvulsant drugs in patients free of seizures for two years. New England Journal of Medicine, 318,942-946. Camfield, P R., Camtield, C. S., Smith, E. C., & Tibbles, J. A. R. (1985). Newly treated childhood epilepsy: A prospective study of recurrences and side effects. Neurology, 35.722-725. Choonara, 1. A., & Rane, A. (1990). Therapeutic drug monitoring of anticonvulsants. State of the art. Clinical Pharmacokinetics, 18, 318-328. CoIlacott, R. A., Dignon, A., Hauck, A., & Ward, J. W. (1989). Clinical and therapeutic monitoring of epilepsy in a mental handicap unit. British Journal of Psychiatry, X5,522-525. Corbett, J. A., Trimble, M. R., & Nichol, T. C. (1985). Behavioral and cognitive impairments in children with epilepsy: The long-term effects of anticonvulsant therapy. Journal of the American Academy of Child Psychiatry, 24.17-23. Cord Laboratories, Inc. (1989). Package insert for chlorpromazine hydrochloride syrup, USP oral solution (concentrate) tablets, USP. (7020, C89/3). Broomfield, CO: Author.
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Cramer, J. A., Smith, D., Mattson, R. H., De&ado Escueta, A. V., Collins, J. F., & the VA Epilepsy Cooperative Study Group (1983). A method of quantification for the evaluation of antiepileptic drug therapy. Neurology, 33 (Suppl.), 26-37. Fischbacher, E. (1987). Prescribing in a hospital for the mentally retarded. Journal of Mental Deficiency Research, 31.17-29. Gadow, K. D. (1986). Children on medication (Vol. 2). Epilepsy, emotional disturbance, and a&rlescent disorders. San Diego: College-Hill. Garnett, W. R. (1989). Epilepsy. In J. T. DiPiro, R. L. Tabert, B. E. Hayes, G. C. Yees, & L. M. Posey (Eds.), Pharmacotherapy: A pathophysiologic approach (pp. 611-631). New York: Elsevier. Gay, P. E. (1984). Effects of antiepileptic drugs and seizure type on operant responding in mentally retarded persons. Epilepsia, 25, 377-386. Gram, L., Bentsen. K. D., Parnas, J., & FIachs, H. (1982). Controlled trials in epilepsy: A review. Epilepsia, 23.491-519.
Gualtieri, C. T., Schroeder, S. R., Hicks, R. E., & Quade, D. (1986). Tardive dyskinesia in young mentally retarded individuals. Archives of General Psychiatry 43, 335-340. Hill, B. K., Balow, E. A., & Bruininks, R. H. (1985). A national study of prescribed drugs in institutions and community residential facilities for mentally retarded people. Psychopharmacology Bulletin, 21, 279-284.
Iivanainen, M., & Savolainen, H. (1983). Side effects of phenobarbital and phenytoin during longterm treatment of epilepsy. Acta Neurologica Scandinavica, 68 (SuppI.), 49-67. Intagliata, J., & Rinck, C. (1985). Psychoactive drug use in public and community residential facilities for mentally retarded persons. Psychopharmacology Bulletin, 21,268-278. Jonas, 0. (1980). Pattern of drug prescribing in a residential centre for the intellectually handicapped. Australian Journal of Developmental Disabilities, 6,25-29. Kutt, H. (1984). Interactions between anticonvulsants and other commonly prescribed drugs. Epilepsia, 25 (Suppl.), 118-131. Linnoila, M., Viukari, M., Vaisanen, K., & Auvinen, J. (1980). Effect of anticonvulsants on plasma haloperidol and thioridazine levels. American Journal of Psychiatry, 137, 819-821. Lipman, R. S. (1982). Psychotropic drugs in mental retardation: The known and the unknown. In K. D. Gadow & I. Bialer (Eds.), Advances in learning and behavioral disabilities (Vol. 1, pp. 261-282). Greenwich, CT JAI Press. Martin, J. E., & Agran, M. (1985). Psychotropic and anticonvulsant drug use by mentally retarded adults across community residential and vocational placements. Applied Research in Mental Retardation, 6, 33-49.
McEvoy, G. K. (Ed.) (1989). American hospital formulary service. Bethesda, MD: American Society of Hospital Pharmacists. McGowan, M., NeviIle, B. G. R., & Reynolds, E. H. (1983). Comparative monotherapy in children with epilepsy. British Journal of Clinical Practice, 27 (Suppl.), 115-118. Pulman, R. M., Pook, R. B., & Singh, N. N. (1979). Prevalence of drug therapy for institutionalized mentally retarded children. Australian Journal of Mental Retardation, 5,212-214. Remick, R. A., & Fine, S. H. (1979). Antipsychotic drugs and seizures. Journal of Clinical Psychiatry, 40, 78-80.
Schmidt, D. (1983). Reduction of two-drug therapy in intractable epilepsy. Epilepsia, 24, 368-376.
Shinnar, S., Vining, E. P. G., Mellits, E. D., D’Souza, B. J., Holden, K., Baumgardner, B. A. (1985). Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. New England Journal of Medicine, 313,976980. Shorvon, S. D., & Reynolds, E. H. (1977). Unnecessary polypharmacy for epilepsy. British Medical Journal, 1, 1635-1637. Sovner, R., & DesNoyers Hurley, A. (E&s.) (1982). Psychotropic drug interactions with anticonvulsants. Psychiatric Aspects of Mental Retardation Newsletter; 1, 17-23.
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Stone, R. K., Alvarez, W. F., Ellman, G., Horn, A. C., & White, J. F. (1989). Prevalence and prediction of psychotropic drug use in California developmental centers. American Journal on Mental Retardation, 93,627-632.
Vming, E. P. G., Mellits, E. D., Dorsen. M. M., Cataldo, M. F., Quaskey, S. A., Spielberg, S. P (1987). Psychological and behavioral effects of antiepileptic drugs in children: A double-blind comparison between phenobarbital and valproic acid. Pediatrics, 80, 165174. White, A. J. R. (1983). Changing patterns of psychotropic drug use with the mentally retarded. New Zealand Medical Journal, 96,686-688. Wolfe, S. M., & Forsythe, A. (1978). Behavior disturbance, phenobarbital, and febrile seizures. Pedintrics, 61,728-731.
