Maria G. Valdovinos
Deborah A. Napolitano
University of Rochester School of Medicine
Strong Center for Developmental Disabilities
In recent years, there has been an increasing emphasis on translational research in behavior analysis (Lerman, 2003). Traditionally, behavioral scientists have been effective in using the principles of behavior to affect behavior change, most notably in the treatment of problem behaviors such as aggression, self-injury, and non-compliance. Over the past 20 years, there has been an increased understanding of the mechanism of action of various psychotropic drugs, how they affect the organism, and how they affect environmental variables that control behavior (Branch, 1984; Napolitano et al., 1999; Schaal & Hackenberg, 1994; Schroeder, Lewis, & Lipton, 1983).
Traditionally, the use of anticonvulsants has been limited to seizure control; however, anticonvulsants have been found to have mood stabilizing qualities and are now prescribed to treat bipolar disorder in addition to seizure disorders (Gajwani et al., 2005). In people with developmental disabilities, anticonvulsants are used to treat seizure disorders and as a pharmacological intervention for behavior problems (Matson, Luke, & Mayville, 2004). Often then, the best treatment option for problem behavior in developmental disabilities is the combined use of a psychotropic drug, such as an anticonvulsant, and behavioral treatment (Napolitano, et al., 1999; Valdovinos, Schroeder, & Kim, 2003).
The purpose of this paper is to provide a brief review of basic behavioral pharmacology research on conventional anticonvulsants drugs. Much of this basic work is conducted with animals; however, this work is relevant for understanding behavioral mechanisms affected by anticonvulsant drugs. Additionally, applied and clinical behavioral research on the use of anticonvulsants for behavior reduction in developmental disabilities is reviewed. This review focuses primarily on the effects of anticonvulsants on performance during various schedules of reinforcement, on avoidance responding, and functional relations; however there was little information on these effects in the applied literature. The translational implications of this research on treatment and recommendations for conducting translational research between behavioral pharmacology and applied behavior analysis are provided.
As previously discussed, anticonvulsants are primarily prescribed to treat seizure disorders, however, current indications in persons with developmental disabilities also includes mood disorders and problem behavior. The most common anticonvulsants used as mood stabilizing drugs with people with developmental disabilities include: carbamazepine (Tegretol), valproic acid (i.e., divalproex sodium, valproate) (Depakote), lamotrigine (Lamictal), and gabapentin (Neurontin) (Olson, Hellings, & Black, 2003). Other anticonvulsants have been studied within the basic area. These include: ethosuximide (Zarontin), phenobarbital, phenytoin (Dilantin), methsuximide (Celontin), and mephenytoin (Mesantoin). These drugs vary with regards to the mechanism of action. For example, valproic acid involves increased turnover of the neurotransmitter ?-aminobutyric acid (GABA) whereas carbamazepine involves inhibiting cyclic adenosine monophosphate (cAMP) formation (Kowatch & Bucci, 1998), a second messenger responsible for gating ion channels and phosphorylation of third messenger proteins for various neurotransmitters and hormones.
Review of Basic and Applied/Clinical Research
A literature search was conducted using ERIC, Medline, PsychINFO, and PubMed. Our search was limited to the English language. Additional articles were identified from the reference lists of previously identified articles. Terms used to identify basic research articles were anticonvulsant, schedule, and responding. Terms used to identify applied/clinical research articles were anticonvulsant, mental retardation, developmental disabilities, aggression, and autism. Studies in which the primary purpose was to evaluate the effects of the medication on seizures were excluded. Also excluded from this review were benzodiazepines. Although they are also used to treat seizure disorders and behavior problems, they are generally classified as anxiolytics.
In our review of the basic literature, we focused primarily on those studies that evaluated drug effects on appetitive and avoidance responding. Several different methods for evaluating the effects of anticonvulsants on responding were used. As a result, anticonvulsants will be discussed in terms of similarities and differences in schedule effects as described in the published literature.
The review of applied/clinical research primarily focused on decreases in problem behavior (e.g., aggression) or increases in appropriate behavior (e.g., social skills). Often, the effects on the contingencies involved (e.g., reinforcement) or functional relations were not directly measured. These effects were sometimes inferred by the reviewers based on the description of the results provided by the authors. Typically these changes were observed or measured through naturalistic observation, standardized assessment, and less often by functional analyses. Despite differences in methodology between basic and applied research, an attempt will be made to compare the findings in order to make some recommendations for researchers and clinicians.
Review of Basic Research
The most common schedules used in basic research included fixed ratio and interval (FR and FI) and variable interval schedules of reinforcement (VI), fixed-consecutive number (FCN) schedule, inter-response time (IRT), avoidance tasks, and delayed-matching-to-sample and repeated acquisition. The most common medications evaluated were carbamazepine, valproic acid, phenytoin, and phenobarbital.
Effects of anticonvulsants on responding on fixed ratio and interval schedules. Through a series of studies, researchers determined the effects of methsuximide and mephenytoin on schedule-controlled responding in pigeons using FR and FI schedules of reinforcement (Delaney, Pellettiere, Schlinger, & Poling, 1988; Pellettiere, Delaney, Schlinger, & Poling, 1988). Only when the highest doses of methsuximide (100mg/kg) and mephenytoin (240 mg/kg) were administered, did rates of responding decrease under both the FR and FI schedules; however, there did not appear to be dose-dependent decreases in responding. Tolerances to the rate-decreasing effects of methsuximide and mephenytoin also were observed to occur in this study. Additional studies evaluated the effects of valproic acid, ethosuximide, phenytoin, and phenobarbital under different schedules of reinforcement (Kraft & Poling; Picker, Thomas, Koch, & Poling, 1985; Picker, Leibold, Endsley, & Poling, 1986; Poling, Picker, Grossett, & Vande Polder, 1985; Renfrey, Schlinger, Jakubow, & Poling, 1989). Using pigeons, Poling, Picker et al. (1985) found that neither valproic acid nor ethosuximide produced rate-dependent decreases in responding on an FR50 and FI90 schedule of reinforcement. Krafft and Poling (1982) found that 10mg and 20mg of phenytoin decreased responding on an FR50 schedule in a dose-dependent fashion, however, the greatest effects were time sensitive. That is, the 10mg dose produced the greatest decreases in responding in the pigeon when administered 45-m before the session and not sooner or later.
Effects of anticonvulsants on responding on variable interval schedules. Caruso and colleagues (2002) evaluated the effects of carbamazepine on responding on a VI positive reinforcement schedule. Their results indicate a dose-dependent decrease in responding on the VI schedule for all doses tested with the exception of the highest dose (which resulted in a statistically significant decrease in responding which was attributed to general sedation). Another study evaluated the effects of carbamazepine on response choice between varying delays of reinforcement in rats (Evenden & Ryan, 1996). Carbamazepine did not affect response choice within this paradigm. That is, rats pressed the lever that was associated with larger reinforcers when the delay was smaller and pressed that lever less as the delays increased when on saline and two doses of carbamazepine. Other studies evaluated the effects of methsuximide and mephenytoin on the reaction time of pigeons (Blakely, Starin & Poling, 1989). In this study, when presented with an initial visual stimulus (white light), pigeons were trained to depress a pedal and when presented with a second visual stimulus (red light), pigeons were trained to release the pedal. The duration of time the white light remained lit was variable with a mean of 1.75 seconds. Both drugs were associated with a dose-dependent increase in response time (the amount of time between the presentation of the red light and the release of the lever) and decrease in percentage of responses reinforced were observed, however, there appeared to be stronger tolerance effects observed in those pigeons administered mephenytoin than methsuximide.
Effects of anticonvulsants on responding on fixed consecutive number schedules. Picker et al. (1986) evaluated the effects of valproic acid, phenytoin, and phenobarbital on the performance of pigeons on a FCN 8 schedule. On this schedule, the response requirement was between 8 to 12 pecks on the work key and then 1 peck on the reinforcement key for 3-s access to mixed grain, any other patterns of responding resulted in a 2-s timeout. Pigeons were assigned to one of two groups. For the first group (FCN 8), the color of both keys was white and for the second group (FCN-8SD), the work key was red and the reinforcement key was white. During control there were more reinforced runs for FCN-8SD than on the FCN 8 schedule and for the drugs tested, the greatest decreases in reinforced runs on both schedules were seen when phenobarbital was administered. Administration of phenytoin and valproic acid resulted in only slight decreases in reinforced runs on the FCN 8 and FCN-8SD schedules.
Effects of anticonvulsants on responding during inter-response time. Picker et al. (1985) evaluated the effects of phenytoin, phenobarbital, and valproic acid alone and in combination on responding under FR30 and IRT greater than 15-s schedules of reinforcement in rats. Under the FR30, a dose-dependent decrease was observed for all drugs administered separately. Under the IRT>15-s schedule, no effects were observed although effects on mean reinforcement rates were observed. In a different experiment, phenytoin resulted in significant decreases in responding on a multiple FR30 IRT>10-s schedule in dose-dependent fashion whereas phenobarbital did not (Renfrey et al., 1989).
Effects of anticonvulsants on responding on avoidance tasks. In a series of studies using rats, Banks et al. (2001) and Banks, Mohr, Besheer, Steinmetz, and Garraghty (1999) evaluated the effects of two different anticonvulsants (carbamazepine and phenytoin) at a single dose on an FR4 schedule of reinforcement and an avoidance task that required the rat press a bar during the first 3-s of the presentation of an auditory stimulus (tone) to avoid a shock or press the bar 3-s into the presentation of a shock to escape the shock. There were two groups of rats that participated in the avoidance component of the study. The first group had experience with appetitive responding and the second group did not. Researchers found a decrease in responding on the avoidance schedule for the appetitive-schedule naïve rat but did not for the group of rats that had experience with appetitive responding. In a different study conducted with mice, researchers also found that the administration of carbamazepine and phenytoin produced decreases in avoidance responding (Voigt & Morgenstern, 1996). Caruso et al. (2002) also evaluated the effects of carbamazepine on responding on a free-operant avoidance task. The results revealed static responding on the avoidance task for all doses tested; with the exception of the highest dose (this was consistent with their findings for performance on the VI schedule). These differing results suggest that new learning may be impaired while on the drug although established behaviors may remain unaffected.
Effects of anticonvulsants on responding during delayed-matched-to-sample and repeated acquisition tasks. With regards to learning and memory, anticonvulsants have also been studied to determine the extent of deleterious effects on both learning and memory. Repeated acquisition tasks were conducted to assess the effects of acute and chronic administration of phenytoin, ethosuximide, and valproic acid on responding in pigeons (Poling, Blakely, White, & Picker, 1986). Acute dosing resulted in reduced response rates in a dose-dependent fashion for phenytoin and ethosuximide and variable effects for valproic acid and very little effect was observed for accuracy for phenytoin and valproic acid. Chronic dosing resulted in tolerance to the effects observed during acute administration for all the drugs tested. In an evaluation of the effects of carbamazepine on responding during repeated acquisition in rats, low doses of the drug resulted in increased response rates and a decrease in errors made whereas the high doses resulted in the opposite. A series of studies were conducted evaluating the effects of ethosuximide, phenobarbital alone, valproic acid, phenytoin, and phenobarbital in combination with phenytoin and valproic acid on performance of pigeons on a delayed-matching-to-sample procedure or tests of memory (Alling, Nickel, & Poling, 1991; Karas, Picker, & Poling, 1986; Poling et al., 1992). For ethosuximide and phenobarbital, no decreases in response accuracy were observed between the control conditions and drug conditions with the exception of the highest dose. For the remaining drugs, when administered separately, the highest dose resulted in a decrease in accuracy of responding. When presented in combination, the drugs resulted in marginal changes in accuracy compared to the drugs given separately.
All of the studies reviewed in the basic literature demonstrate that the various anticonvulsants have varying effects on responding on differing schedules of reinforcement. Generally speaking, all anticonvulsants result in some suppression of responding; however, the extent to which responding is suppressed, the conditions under which responding is suppressed, and the tolerance to response suppression varies greatly across the drugs evaluated. Furthermore, for a majority of the studies reviewed, very little mention was made of potential side effects (i.e., sedation) that could be responsible for the decrease in responding observed.
Review of Applied/Clinical Research
Research has demonstrated that anticonvulsants are effective in treating aggression in the general population (e.g., Stanford et al., 2005). Clinical research also has demonstrated that anticonvulsants are effective in treating aggression in individuals with developmental disabilities such as autism (Lindenmayer, & Kotsaftis, 2000; McDougle, Stigler, & Posey, 2003; Tuchman, 2004). Additional research has shown that anticonvulsants may also positively affect social skills. Unfortunately, well-controlled evaluations are rare (Kerr, 2002) and those that do exist provide little information on the effects of anticonvulsants on functional relations in applied settings in people with developmental disabilities.
We found two studies evaluating the effectiveness of a behavioral intervention and delivery of anticonvulsants in combination and anticonvulsants alone for aggression. The first study evaluated the effects of carbamazepine and a behavioral intervention [disruption of aggression, redirection, and differential reinforcement of other behavior (DRO)] using an ABAB design (Rapport, Sonis, Fialkov, Matson, & Kazdin, 1983). Results revealed that the greatest decreases in aggression were obtained when carbamazepine was administered in combination with the behavioral intervention. The second study evaluated the effects of carbamazepine and phenytoin in combination with punishment procedures using a BABCBCB design within a multiple-baseline design across problem behaviors (Dixon, Helsel, Rojahn, Cipoolone, & Lubetsky, 1989). While on carbamazepine, the punishment procedures were implemented during BABC conditions. Carbamazepine was discontinued, a period of no drug followed, and then phenytoin was initiated during the third B condition. Finally, there was a no drug period during the final CB conditions. Although the authors failed to demonstrate control over problem behavior, decreases in problem behavior were observed to occur when carbamazepine and phenytoin were discontinued (phenytoin was associated with an increase in problem behavior).
Perhaps the best studied anticonvulsant for the treatment of behavior problems in the population of people who have developmentally disabilities is valproic acid. In a retrospective study, Ruedrich and colleagues (1999) reported that valproic acid generally appeared to be well-tolerated and effective in decreasing aggression and self-injury in people with developmental disabilities. Another retrospective study found that valproic acid also reduced aggression, mood instability, and impulsivity in children with autism (Hollander, Dolgoff-Kaspar, Cartwright, Rawitt, & Novotny, 2001). Finally, decreases in aggression were reported to occur for two individuals diagnosed with mental retardation (mild and profound) (Mattes, 1992).
Two studied reviewed examined the effects of topiramate on problem behaviors (Janowsky, Kraus, Barnhill, Elamir, & Davis, 2003; Smathers, Wilson, & Nigor, 2003). While Janowsky et al. (2003) evaluated the effects of the medication for persons generally diagnosed with an intellectual disability across a variety of problem behaviors (e.g., hitting, self-biting), Smathers et al. (2003) evaluated the effects in persons diagnosed with Prader-Willi Syndrome, a genetic disorder often associated with mental retardation. The results of the retrospective, open-label study by Janowsky et al. (2003) suggested a statistically significant decrease in problem behaviors. Similar to these results, Smathers et al. (2003) found that all seven participants who continued throughout the study on the drug had improvements in mood, and decreases in aggressive and self-injurious behavior. Additionally, the authors suggested that there was an increase in positive behaviors. The authors theorized that these effects were due to the possible mechanism of action for topiramate, such as the enhancement of GABA-ergic activity.
Anticonvulsants may also have an effect on pro-social behaviors. In one review (e.g., Matson et al., 2004), it was suggested that phenytoin might have effects on attention and motor abilities. Matson et al. (2004) examined the behavioral effects of phenytoin, carbamazepine, and valproic acid. The authors reported that phenytoin had a negative effect on social behavior that could possibly be explained by impaired attention and motor abilities. This could result in decreases in learning as reported by Banks et al. (1999; 2001), with carbamazepine and phenytoin. Matson et al., (2004), however, also reported that carbamazepine and valproic acid appeared to have no effect on social behavior. Conversely, Hollander, Dolgoff-Kaspar, Cartwright, Rawitt, and Novotny (2001) described an open, retrospective study of the effects of divalproex sodium on the core features of autism and other associated problems (e.g., aggression). In addition to decreases in aggression and impulsivity, participants also showed increases in social skills such as social relatedness and listening.
Although most studies have reported positive or lack of negative effects with anticonvulsant medications, Ettinger et al. (1998) reported varying effects across participants for lamotrigine. One participant showed decreases in hyperactivity and increases in compliance, indicating that lamotrigine might have decreased negatively reinforced responding. A second participant showed increases in hyperactivity, decreases in compliance, and increases in irritability. A third participant demonstrated increased crying, screaming, and hyperactivity. In a different study, out of 19 participants, lamotrigine treatment resulted in increased aggression for 9 individuals and increases in other behavior problems for 4 individuals (Beran & Gibson, 1998). Although these are only two studies, clearly the effects of lamotrigine on behavior are not consistent. However, these varied results are not inconsistent with the effects of lamotrigine as observed in the general population (Gjwani et al., 2005).
Data reviewed demonstrates that anticonvulsants are mixed in their effects on problem and social behavior. In some cases, researchers have reported negative effects such as increases in aggression (e.g., Beran & Gibson, 1998) and in others the results have been more positive and shown decreases in aggression (e.g., Janowsky et al., 2003). Additionally, anticonvulsants have been shown to have a positive effect on some of the core features of autism, such as social skills (e.g., Hollander et al., 2001).
The effects of anticonvulsants on behavioral contingencies need to be examined further. Given that the drugs within this class vary greatly in their mechanisms of action than drugs in other classes, these drugs may have more varying and contrasting effects on behavior than any other drug class. We suggest that applied behavior analysts conduct research on the effects of anticonvulsants on functional relations and that they look to the behavioral pharmacology literature to determine if there are current findings that may promote their own research or understanding of the applied/clinical work that they conduct. For example, would medications that showed dose-dependent decreases in responding in pigeons on a variable schedule (e.g., carbamazepine; Caruso et al., 2002) impact the effects of positively reinforced problem behavior? Another question that may be asked is whether or not dose changes impact behavioral contingencies already in place. Analogue-functional analyses might be a useful tool for examining the relation between anticonvulsants and environmental variables, such as avoidance responding, (Schaal & Hackenberg, 1994), however, this can be tedious work when studying drugs that require long periods of time to reach therapeutic levels and to metabolize (Crossland et al., 2003; Zarcone et al., 2004).
Recently, increased emphasis has been placed on the translation of research traditionally conducted by experimental researchers to applied and clinical arenas which is evidenced by recently published book chapters (e.g., Wacker, 2000) and articles in the Journal of Applied Behavior Analysis (e.g., Lerman, 2003; Mace, 1996). Pharmacology research has determined the mechanism of action of various drugs prescribed to affect problem behavior in people with developmental disabilities. Behavioral pharmacology research has determined the effects of drugs on scheduled responding and additional behavioral assays (e.g., open field, light/dark tests). The next level of analysis needed is for behavior analysts to evaluate changes in functional relations when on drugs.
Finally, there is a great need for translational research between neuroscience, pharmacology, and behavior analysis to gain a better understanding of the relation between the brain, behavior, and the environment and how drugs affect this relation. This need has recently been emphasized with regards to the use of psychotropic drugs in children and adolescents (Vitiello, Heiligenstein, Riddle, Greenhill, & Fegert, 2004). Our last recommendation is that behavior analysts learn about the new advances in neuroscience that allow us to observe and measure what is occurring inside an organism and to also expand on the methodologies currently used by behavior analysts as we continue to measure overt responses (Critchfield, 2002).
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