Clinical trials of D1 and D2 dopamine modulating drugs and self-injury in mental retardation and developmental disability

MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 1: 120-129 (1995)

CLINICAL TRIALS OF DIAND D2 DOPAMINE MODULATING DRUGS AND SELF-INJURY IN MENTAL RETARDATION

AND DEVELOPMENTAL DISABILITY Stephen R. Schroeder, Ron G. Hammock, James A. Mulick, Johannes Rojahn,

Philip Walson, Will Fernald, Patricia Meinhold, and Geeta Saphare The University ofKansas, Lawrence, Kansas (S.R.S., R.G.H.); The Ohio State University (J.A.M., J.R., P.W., P.M., G.S.);

Heinzerling Developmental Center, (W.F.), Columbus, Ohio

We review the rationale for conducting clinical trials of D1 and Dz dopamine modulators for self-injurious behavior (SIB) among people with mental retardation and developmental disabilities. We include a brief history of the relevant behavioral research on SIB, the psychopharmacology of neuroleptic drugs for SIB, pharmacotherapy for SIB based on dopamine function, treatment for SIB with neuroleptics, SIB and dopamine supersensitivity, and the D1 dopamine hypothesis and SIB. We also present controlled case studies of the use of clozapine to treat chronic, refractory SIB in three individuals with profound mental retardation. One was a dramatic responder at 225 mg per day; one was a partial responder at 300 mg per day; and one showed a decrease in stereotypy, but not SIB, at 100 mg per day. Studies from rats, monkeys, and humans support the hypothesis that the D1 dopamine receptor system in the nigrostriatal pathway of the basal ganglia plays a key role in SIB in somecases. o 1995wiley-Liss. Inc. MRDD Research Reviews 1 : 120-1 29

Key Words: self-injurious behavior, clozaphine, dopamine, mental retardation, humans

elf-injurious behavior (SIB) refers to acts directed toward one’s self that result in tissue damage [Tate and Baroff, S 19661. In the psychiatric literature, such behavior is often

treated under the more general heading of self-mutilation and suicidal behavior [Favazza, 1987; Winchel and Stanley, 19911. It is uncertain, at present, whether this classification is behaviorally or neurochemically justified within the population of those with mental retardation and developmental disabilities (MRDD). Although the neurochemistry and psychopharmacology of SIB seem to be linked in this population and in the broader psychiatric population (for review, see Psychopharmacology Bulletin, 19891, the behavioral forms and functions of SIB seem rather distinct in those with MRDD.

For the past two decades, there has been wide agreement that SIB is multiply caused and multiply affected [Baumeister and Rohngs, 19761. It is not a homogeneous response class. SIB has a prevalence of 10% in the M R D D population, but it varies as a function of a variety of risk factors [Schroeder et al., 19781: individuals’ level of mental retardation and chronological age,

o 1995 Wiley-Liss, Inc.

and residential setting, the occurrence of seizures, presence of a psychiatric disorder, and the presence of sensory and communication deficits.

There are many forms of SIB topography in MRDD. Rojahn [1994] has reviewed the main prevalence studies from several different countries and found 38 topographies. Factor analyses of 15 of the most frequently described SIB topographies distinguished three main factors: self-hitting or hitting objects; inserting objects into body orifices, such as eye poking, pica, aerophagia, or polydipsia; and self-biting, scratching, pinching, or hair pulling. Two of the 15 topographies (teeth grinding and ruminative vomiting) failed to load substantially on any of these three factors.

There are many functions for which people with MRDD use SIB as a respondent or as an operant response [see Special Issue of Functional Analysis, ]oumal of Applied Behavior Analysis, (1994) for a review]. Broad classes of the functions of SIB are: to signal approach, signal reinforcement, escape or avoid, commu- nicate, express elicited emotions in response to stress, and self-stimulate. These functions have been extensively researched in the literature on behavior analysis and have been reviewed many times. Perhaps the most authoritative recent review is the Consensus Conference on Destructive Behavior published in 1991 [NICHD, 19911.

The developmental course of SIB varies. Onset can occur at any age; cessation can occur at any time. Indeed, for milder forms, which appear to be environmentally induced and comprise about 75% of observed SIB cases, the time course is less than one year [Schroeder et al., 19781. However, for the remaining 25%, the intransigent cases, onset may occur as early as six months of age, increase rapidly between 3 and 23 years, and then decrease in old age. Interestingly, the average mortality rate among those who exhibit SIB does not differ from that among age- and gender-matched controls [Borthwich-DuQ,

Address reprint requests to Dr. Stephen R. Schroeder, Institute for Life Span Study, The University of Kansas, Lawrence, KS 66045-2505.

1994; Wieseler et al., in press]. This is surprising, given the fact that in some cases individuals bang their heads several thousand times per day. Indeed, we are aware of people who have died as a result of SIB. Perhaps our in vivo methods for studying neuropathologies of this type are as yet inadequate. The relative life- threatening consequences of acute and chronic SIB are important areas for future research.

THE PSYCHOPHARMACOLOGY OF NEUROLEPTICS FOR SELF-INJURIOUS BEHAVIOR

Prior to 1980, the psychopharmacology of low-prevalence, high-severity developmental disorders such as SIB primarily centered on the use of neuroleptic drugs [Gualtieri and Keppel, 19851. Although at that time neuroleptics were being used effectively in the treatment of schizophrenics, it appears that their use for behavior control in the M R D D population became widespread without any clear rationale other than trial and error. Lipman [1970] published an influential prevalence study that found exces- sive use of neuroleptics on more than 50% of residents in public residential facilities for people with MRDD. This was followed by another influential review by Sprague and Werry [1971], which seriously questioned the soundness of previous drug research in the M R D D population and set standards for h ture research in this field. Subsequently, medication monitoring programs were intro- duced and minimum effective dosage procedures were required in publicly funded facilities. The results included fewer neuroleptics, less polypharmacy, lower average doses, and removal of unnecessary medications [Schroeder, 19881. However, these practices vary greatly from one facility to the next, so that no nationwide trend is apparent. Today neuroleptics are still the medications most commonly prescribed to control behavior in the MRDD population [Baumeister et al., 19931.

RATIONAL PHARMACOTHERAPY FOR

BASED ON DOPAMINE FUNCTION

Given the complex dynamics of SIB, including the multiple behavioral and biological causes and the multiple effects, contributing risk factors, and topographies, as well as varying time

SELF-INJURIOUS BEHAVIOR

courses, it is no surprise that it is very dificult to provide rational pharmacotherapy for it. That effort means trying to use drugs that, if misused, are potentially lethal on a high-risk population who usually cannot give informed consent except through an intermediary. One can anticipate a host of methodological problems: lack of adequate sample size, extreme subject heterogeneity, subject attrition, idiosyncratic all-or-none responses, and lack of specific treatment effects on individual subjects, not to mention the ethics of using placebo or control groups that consist of waiting

Prior to 1980, the psychopharmacology of

1 o w-p reval ence, high-severity

developmental disorders such as SIB primarily centered on the use of

neuroleptic drugs [Gualtieri and Keppel, 1985’. Although at that time neuroleptics were

being used effectively in the treatment of

schizophrenics, i t appears that their use for behavior

control in the MRDD population became

widespread without any clear rationale other than

trial and error.

lists, difficulty in maintaining double- blind conditions, and the need to validate acute dose effects ecologically with long- term chronic dose follow-up in the natural environment. No clinical study in this area is without flaws. Nevertheless it is important to conduct open, single- blind, and double-blind trials whenever ethically possible. The studies are needed to justify larger, more definitive studies with rigorously controlled designs, which are necessary to validate the theoretical hypotheses underlying clinical practice. Most of the research on neuroleptics and

SIB is at the level of open and single- blind studies.

TREATMENT OF

WITH NEUROLEPTICS There have been several recent

excellent reviews of the effects of psychotropic medications on aberrant behavior in M R D D paumeister et al., 1993; Thompson et al., 19911, including SIB as seen from a psychiatric [Winchel and Stanley, 19911 and a behavioral stand- point [Aman, 1993; Singh and Milli- champ, 19851. O f the 19 studies reviewed, only three used double-blind cross-over designs. The three most commonly studied neuroleptic drugs were chlorpromazine, thioridazine, and haloperidol. These reviews tend to agree that the results are mixed and inconclusive for these as well as other neuroleptics that have been tested with rigorous methodology; the most favorable evidence is for thioridazine for treating SIB, especially when SIB is stereotyped in form; the clearest effect of neuroleptics is on stereotyped behavior at doses much lower than those commonly used in the psychiatric population; at higher doses, suppression of SIB and other behaviors occurs by sedation.

SELF-INJURIOUS BEHAVIOR

SIB AND DOPAMINE SUPERSENSITIVITY

Numerous lines of evidence suggest that some SIB is a result of supersensitivity of dopamine neurotransmitter systems, especially the nigrostriatal dopamine pathway in the basal ganglia. This evidence comes from studies ofneurolep- tic withdrawal among individuals with SIB, dopamine depletion in the Lesch- Nyhan Syndrome, animal models of stereotyped behavior, and animal models of SIB.

Studies of Withdrawal of Neuroleptics Among SIB Cases

Dopamine supersensitivity was im- plicated in the motor side effects of neuroleptics in schizophrenics due to chronic blockade of dopamine neurons in the basal ganglia. Short-term side effects were acute extrapyramidal side effects such as akithisia, dystonia, and pseudopar- kinsonism. The main long-term side effect is tardive dyskinesia, characterized by involuntary movements of the face, mouth, tongue, upper limbs, and lower limbs. Originally, these side effects were of concern in the schizophrenic population. However, they were later found also in the MRDLI population, in both children [Gualtieri et al., 19841 and adults

MRDD RESEARCH REVIEWS CLINICAL TRIALS OF D1 A N D Dz SCHROEDER ET AL. 121

[Gualtieri et al., 19861. Aberrant behaviors often accompanied such extrapyranudal side effects in a time-locked fashion, suggesting a form of behavioral supersensitivity related to prolonged dopamine blockade. This effect was not restricted to SIB alone, however, so the drug effect was not selective.

Dopamine Depletion in Lesch-Nyhan Syndrome

This syndrome is a sex-linked genetic disorder of purine metabolism [Lesch and Nyhan, 19641. It involves a high incidence of self-biting of fingers, lips, and oral structures in more than 80% of cases. In addition, severe motor dystonia develops, beginning at approxi- mately six months of age and worsening as time passes. These symptoms also are accompanied by an imbalance in serotonergic, dopaminergc, and noradrenergic mechanisms in the brain. Lloyd et al., [1981] in postmortem studies of the brains of three Lesch-Nyhan patients, found a 65-90% functional loss of dopamine terminals and an increase in serotonin terminals in the corpus striatum. These results are consistent with the findings that Lesch-Nyhan patients show decreased dopamine and increased serotonin metabolite excretion in their urine [Sweetman et al., 19771. However, no psychotropic medications, including neuroleptics, have been effective for more than a month or two in treating SIB associated with Lesch-Nyhan syndrome [Nyhan, 19943.

Animal Models of Stereotyped Behavior

A review of stereotyped behavior in people with MRDD by Lewis and Baumeister [1982] was one of the first to identitji dopaminergic supersensitivity as a mechanism for stereotyped behavior, including SIB, in the MRDD population. These authors reviewed a large body of evidence from rodent models on stimulant-induced, opiate-induced, and methylxanthine-induced stereotypy, from primate models of stereotypy induced by isolate rearing, from cage stereotypies, and from displacement activities and schedule-induced stereotypies in a variety of species. All of these point to mediation of stereotyped behavior by the nigrostriatal dopaminergic system. The kind of pharmacologically induced stereotyped activities depends on the chemical agent, the dosage selected, the mode of administration, the amount of environmental stress, the species, the animal’s previous conditioning history, and the genetic

strain, as well as a dynamic balance with related neurotransmitter systems.

How much stereotyped behavior and SIB overlap in humans is uncertain. Several studies [Barron and Sandman, 1983; Rojahn, 1986, 1994; Wieseler et al., 19851 have found that when caregv- ers classitji SIB and stereotypy in terms of their antecedents and consequences, they occur alone about two-thirds of the time and together about one-third of the time. This fact, however, in no way diminishes their common neurochemical relationship, apparently in the nigrostriatal dopamine pathway.

Animal Models of SIB We have previously reviewed ani-

mal models of destructive behavior,

Among the many developmental

implications of the neonatal 6- OHDA

model for SIB [Schroeder and Tessel, 19941, the

one that probably is most important is that it

explains why chlorpromaxine,

haloperidol, thioridaxine, and similar drugs have

not worked very well for SIB in MRDD. These

are all primarily D2-dopamine receptor

blockers.

including aggression, stereotypy, and SIB [Schroeder and Tessel, 1994; Schroeder et al., in press; Tessel et al., this volume]. The primary animal model relating dopamine supersensitivity and SIB is the Breese/Baumeister neonatal dopamine depletion hypothesis.

Breese et al., [1984a] found that rats lesioned in the corpus striatum at 5-15 days of age with the neurotoxin 6-hy- droxydopamine (6-OHDA) suffered a profound loss of striatal dopamine neurons and a correlated increase of striatal serotonin neurons, just as Lloyd et al. [1981] had found in Lesch-Nyhan syn-

drome. If, as adults, these rats were challenged with the dopamine agonist, L-DOPA, they exhibited mutilative self- biting. However, this behavior was not observed in controls or adult-lesioned animals. Breese et al. [1984] proposed this 6-OHDA lesion rat model as a model for Lesch-Nyhan syndrome. This proposal was supported by Goldstein et al., [1986], who found that dopamine agonists can induce self-mutilative behavior in young monkeys with unilateral ventralmedial tegmental lesions that reduce brain dopamine.

Using the neonatal dopamine depletion model, Breese and colleagues conducted a program of research that strongly suggested that D1-dopamine receptors primarily responsible for L- DOPA-induced SIB [for reviews, see Breese et al., 1990 and Breese et al., this issue]. One of their major findings was that the specific D1 antagonist SCH- 23390 blocked L-DOPA-induced self- mutilative biting in neonatally 6-OHDA lesioned rats, whereas haloperidol, a D2 antagonist, did not. The D,-dopamine agonist SKF-38393, when given alone, induced self-mutilative biting in only a portion of the rats that had responded to L-DOPA but, given in combination with a D2 dopamine receptor agonist, SKF- 38393, produced self-mutilative biting in most of the L-DOPA responders. They also found that when neonatally 6-OHDA lesioned rats naive to drug treatment were repeatedly treated with a D1- dopamine agonist, the response to it increased with each treatment. This effect, called priming, changed D1- dopamine responsiveness for as long as 6 months. Priming did not occur with D2 receptor agonists.

These major findings have been replicated by Tessel and colleagues [this issue]. Kostrzewa and Gong [I 9911 have also shown that SKF-38393 produced enhanced oral activity, which appeared to be a precursor to self-biting, in neonatally 6-OHDA lesioned rats. Their research also suggested that supersensitization of this oral response to SKF-38393 is mediated through a serotonin system [Gong et al., 19921. The relationships among the various dopamine and serotonin receptor subtypes to self-biting in the Breese model remain to be worked out but, at present, the primary mediator appears to be the D,-dopamine receptor.

The D1 Hypothesis and the Psychopharmacology of SIB

Among the many developmental implications of the neonatal 6-OHDA model for SIB [Schroeder and Tessel,

122 MRDD RESEARCH hV1EW.S 9 CLIN~CALTRIALS OF D, AND Dl SCHROEDER ETAL.

19941, the one that probably is most important is that it explains why chlorpromazine, haloperidol, thioridazine, and similar drugs have not worked very well for SIB in MRDD. These are all primarily D2-dopamine receptor blockers. Based on the Breese model, it appears that drugs that primarily block D1 receptors would be more successful in decreasing SIB in humans. Unfortunately, there is no pure Dl-dopamine blocking drug available for clinical use in the United States.

Clinical Testing of the Experimental Drug SCH-12679

In the early 1970s, an experimental drug, SCH-12679, was tested as a potential treatment for aggression and SIB in people with MRDD. The results were positive [Itil et al., 1972; Albert et al., 19771. One study [Elie et al., 19801 found that SCH-12679 decreased aggression and SIB, whereas thioridazine increased it in an MRDD population. Unfortunately, the trials of SCH-12679 had to be discontinued because of the side effects of the drug, which never came to market. Recently Breese et al. [1990] have shown that SCH-12679 is primarily a D1-

dopamine receptor blocker.

Clinical Trials With Fluphenazine Fluphenazine is a high-potency

neuroleptic drug often used to treat people with schizophrenia who are non- compliant. It blocks both D l and D2 dopamine receptors, and thus was considered a partial test of the D , hypothesis.

Goldstein et al. [1985] conducted a three-week double-blind crossover study with two Lesch-Nyhan syndrome patients, one 20 months old and the other 15 years old. Fluphenazine had a dramatic effect on the young child, but less effect on the older child; haloperidol had no effect on either child. These results were exactly the ones predicted by the D1 hypotheses. Subsequent trials of fluphenazine, primarily in older children and adults with Lesch-Nyhan syndrome, showed no improvement Uankovic et al., 1988; Nyhan, 19941. N o other trials.of fluphenazine use in very young Lesch- Nyhan patients have been published.

Gualtieri and Schroeder [I9891 conducted a two-year series of open and single-blind dose escalation studies of fluphenazine among institutionalized adults with profound mental retardation and chronic, refractory SIB. Significant and lasting reduction of SIB was found in 10 of 15 individuals. Extrapyramidal side effects occurred in four subjects and, principally when the drug was given at

high doses, severe akithisia occurred in three subjects. Use of the drug for these subjects had to be discontinued. None of these subjects had Lesch-Nyhan syndrome and only three were self-biters, so the D, effect in Lesch-Nyhan syndrome may not be confined to self-biting. Nevertheless, these clinical trials with fluphenazine were discontinued because of the serious side effects subjects experi- enced.

CLINICAL TRIALS WITH CLOZAPINE

This “broad spectrum” drug has been used successfully to treat chronic,

Cloxapine is called an atypical neuroleptic

because its neurochemical and neuro-anatomical properties differ from

those of standard neuroleptics, which have

a high aflnity for D2-dopamine receptors, Clozapine is a relatively potent D1, D3, and 0 4

antagonist, and a less potent D2 antagonist uann, 19911. It also

antagonizes al-adrenergic, a2-adrenergic,

muscarinic, cholinergic, Hl-histaminic, and (5-HT) serotonergic

receptors.

refractory schizophrenia. Clozapine is called an atypical neuroleptic because its neurochemical and neuro-anatomical properties differ from those of standard neuroleptics, which have a high affinity for D,-dopamine receptors. Clozapine is a relatively potent D,, D3, and D4 antagonist, and a less potent D2 antagonist [Jann, 19911. I t also antagonizes a,- adrenergic, a,-adrenergic, muscarinic, cholinergic, Hl-histaminic, and (5-HT) serotonergic receptors [Meltzer, 19911.

MRDD RESEARCH REVIEWS CLINlCAL TRIALS OF D, AND Dz ’ SCHROEDER ET AL.

Unlike typical neuroleptics, it does not cause tardive dyskinesia or other ex- trapryamidal side effects. It can cause a blood disorder that results in a lowered white blood cell count, seizures, dysryth- mia, and agranulocytosis, which can be fatal if undetected. Alvir et al. [1993], however, have shown that the risk is only 0.8% if white blood cell counts are monitored weekly.

Reports of cases in which clozapine has been used in efforts to treat mental retardation schizophrenia, o r severe mood disorder have shown some success [Ratey et al., 1993; Cohen and Underwood, 1994; Pary, 1994; Sajatovic et al., 19941. Most of the individuals treated were mildly retarded with a primary diagnosis of schizophrenia who also exhibited aggressive and, occasionally, SIB. Effec- tive doses ranged from 300-400 mg per day.

There have been no double-blind, placebo-controlled studies of clozapine for SIB in the Lesch-Nyhan syndrome or among the severely or profoundly retarded. Criswell et al. [I9891 found that clozapine blocked self-mutilation in neonatal 6-OHDA-lesioned rats at a dose lower than that commonly used for schizophrenia.

With these results in mind, we began a series of double-blind, placebo- controlled studies of chronic refractory SIB cases. An investigative drug permit was approved by the Food and Drug Administration. That agency’s special surveillance system (The Clozaril Patient Management System) was used to moni- tor side effects.

The inclusion criteria for subjects were that they be 18-50 years old, have moderate to profound mental retardation, have stable general health, taking taking no intercurrent psychotropic medications, participate in an appropriate habilitative environment, and have a long history of SIB. Additional requirements were that subjects had failed to respond to at least two psychotropic medications as well as to behavior management procedures aimed at establishing lasting reduction of SIB without restraints. Subjects also had to be free of seizures, seizure medication, and birth control medication. Infomied consent of parent or guardians was the final criterion. After all 13 of the necessary consents and approv- als had been signed, we were able to recruit one subject in Ohio (Subject A) and one subject (Subject B) in Kansas who met all of the inclusion criteria.

123

clozapine 1Mlmg

\ L

placebo

\

3 4 5 6 7 8 9 10 11 12 13 14 15 Months of Treatment

Fig. 1. Self-injury episodes per day requiring behavior consequences during different phases of clozapine treatment of Subject A.

200

150

100

50

0

...... .

.......

n

li

......................................

I

OPre-81 lClozapine n r.3 Post-81

DEMAND NEGATIVE POSITIVE ALONE

Functional Analysis Conditions Fig. 2. Average frequency of SIB during clozapine treatment under four functional analysis conditions for Subject A.

Subject A meningitis, which she had at the age of This 34-year-old Caucasian woman three years. Her parents were both

had a diagnosis of cerebral palsy and deceased and guardianship had been spastic diplegia. Her intercurrent medica- transferred to a public corporation in tions were sodium docusate and ibupro- Ohio. The subject was not ambulatory fen. The etiology of her profound mental and needed assistance by staff for transpor- retardation was probably related to spinal tation in a wheelchair.

Her SIB consisted in hitting her nose with her fists, hitting her head with her hands, and pressing her face hard against table edges. A large scab and considerable scar tissue were usually in evidence on the bridge of her nose as a result of her repeated self-injury. Hers was a very serious but low-frequency type of SIB.

The subject functioned at a 5%- to 6x-month level on the Bayley Scales of Infant Development, with scatter to higher age levels. According to the Vineland Adaptive Behavior Scales, she functioned at the level of 9 months in Communication; 1 % years in Daily Liv- ing Skills; 5 months in Socialization; and 10 months in Motor Skills. She had an Adaptive Behavior Composite of 11 months. She was reported to understand the meaning of about 10 words and to be able to follow very simple instructions involving only one action. She was able to gesture to indicate yes or no and to request something, she vocalized sponta- neously, and occasionally used single words for requests. She was cooperative with most daily living skills, but needed consistent supervision in meeting her daily wants and needs.

The setting for the clinical trial was a private residential facility certified as an ICF/MR and designed to serve the needs of nonambulatory people with severe developmental retardation. Behavioral observations were recorded by unit staff. Behavior ratings were recorded by unit staff, unit nurses, and physicians. Throughout the protocol, videotapes were recorded during evening samples of behavior conducted Monday through Friday. However, analysis of these tapes revealed little of interest because SIB was rarely recorded on them.

Structured functional-analysis sessions were conducted and videotaped during each major phase of the clinical trial. The sessions involved systematic alteration of environmental conditions in an attempt to obtain differential rates of behavior. Four conditions were presented in a counterbalanced Latin squares order each session across observation weeks. The conditions consisted of 3-minute segments, 4 per session, of Alone, High Demand, Negative Atten- tion, and Positive Attention. During the Alone condition, the subject was videotaped without social interaction and with no objects on her lapboard. During the Demand condition, a series of simple commands involving a consistent set of objects was repeated in a fixed series. The subject was told to stack blocks, place small objects in a box, and perform motor

124 MRDD RESEARCH REVIEWS CLINICAL TRIALS OF DI AND Dl SCHROEDER ETAL.

and vocal imitation. She was given hand-over-hand guidance if compliance did not occur with 5 seconds of a command or if the behavior stopped during performance. During the Nega- tive condition, SIB or other misbehavior was reprimanded if it occurred. Standard toys were available during this condition. Finally, the Positive condition consisted of free play with standard toys, during which praise and enthusiastic description of the subject’s behavior with respect to the play material was the only form of interaction between the subject and the research assistant who conducted the sessions. The sessions were conducted in a room measuring 9 X 12 feet. The room had no windows. The subject was seated in a wheelchair behind a small table. The video camera was mounted on a tripod. The number of people present in the room and the material placed on the table varied as a function of the condition in effect.

The videotapes were scored after completion of all data collection by research assistants who did not know which drug condition was in effect at the time of the recording. Interrater reliability was determined by having two observers record data from the videotape on separate computer keyboards at the same time. Agreement, calculated by the formula agreements + disagreements/ total observations X 100, was found to be acceptable, averaging over 80% for all categories.

The clozapine trial was designed to provide experimental control while at the same time assuring consistent clinical care for the subject. A flexible single-subject dose escalation design was put into effect [Sheiner et al., 19891. This design was manipulated by the responsible physician and interdisciplinary treatment team in collaboration with a researcher (data coordinator). Both the physician and the researcher remained nonblind with regard to the protocol status. The physician was responsible for the general health of the subject and for final decisions regard- ing changes in the clozapine prescription. He was advised by the researcher, who collated the weekly data and discussed them with the clinician once a week. The data coordinator then informed the off- site pharmacist of the clinical decision, who then prepared the dosage regimen for the following week and packed the capsules in a cassette for daily dispensing by nursing staff at the residential facility.

The trial began with a baseline, which lasted 10 weeks. This was followed by a double-blind two-five-week placebo-controlled baseline, the duration of

which was known only to the physician, the data manager, and the pharmacist. After three weeks of placebo, a step-wise clozapine titration was begun, starting with 5 mg bid dose, which was incremen- tally increased each week until 50 mg bid was reached. At that point, the clinical team decided to discontinue the trial. The subject was tapered off clozapine using the same titration schedule.

All the data were collected by direct-care and professional staff from the client’s residential facility, all of whom were unaware of the exact begnning of the drug titration. Three scales were used as primary dependent variables to moni- tor drug effects. Drug effects were investigated with an instrument for a broad spectrum of generic behavior problems and two instruments that fo- cused on the specific target behavior exhibited by the client. These instm- ments included the Aberrant Behavior Checklist [Aman and Singh, 19851 and the Maladaptive Behavior Scales. (MABS) [Thompson, unpublished], which were filled out weekly by the stag the one-hour videotapes recorded daily between 4:00 and 7:OO p.m. and scatter plots of SIB [Touchette et al., 19851; Clinical Global Impressions, Neuroleptic Side Effects Checklist, Simpson-Angus EPS Rating Scale, and Abnormal Invol- untary Movement Scale [National Insti- tutes of Mental Health, 19831, all administered weekly, and weekly venous blood samples, all completed by the nursing staff.

The results were that clozapine had essentially no effect on SIB for Subject A on any of the measures, because the rates of occurrence of SIB were so low. When baseline rates are low, it is often difficult to see a drug effect. Behavior management summary data for the Ohio clozapine subject, shown in Fig. 1 indicate another interesting pattern. When the baseline was being recorded for the clozapine trial, the subject had a mean rate of 3.5 instances of SIB per day that were severe enough to require initiation of a behavior management procedure. The decrease in the rate of occurrence coincides with the placebo phase of the double-blind clinical trial. The other uncharacteristic decrease corresponds with the decision to discontinue the drug completely. In other words, the only two deviations from a gradually decreasing rate of SIB severe enough to trigger behavior management procedures occurred at times when staff were likely to become more reactive to this patient’s behavior because some decision had been made by the experimenters. In the first

case, the beginning of the placebo phase appeared to direct care staff as though use of a drug had been started. In the second case, open discussion of the patient’s status was required in order to decide, on a clinical basis, whether or not the drug should be maintained beyond the end of the trial. This is consistent with no drug effect on SIB. It is also interesting that the decline in the SIB reflected by this measure continued well past the time of complete drug withdrawal and after drug metabolites were eliminated from the subject’s body. This result emphasizes the need for blind conditions to guard against potential staff reactivity.

The analog functional analysis sessions revealed only one consistent effect, that on stereotypy, which seemed to be related to the administration of clozapine. This effect on stereotypy is depicted in Fig. 2 , which shows the total number of stereotypic behaviors (defined as an in- stance of at least three repetitions of the same act or movement sequence with no apparent interactive function) plotted in histograms for the placebo baseline, the clozapine phase as a whole, and the post-clozapine baseline as a function of stimulus condition. It appears that these data indicate a clear suppressive effect of clozapine on the rate of stereotypy for our subject, but only during the Demand and the Alone conditions of observation. She performed virtually no stereotypy during the brief analog sessions during these two stimulus conditions. Stereotypy was less clearly related to suppression of stereotypy in the two Positive and Negative attention stimulus conditions. These data are consistent with an active drug effect of clozapine on our subject, which is also consistent with the effects of other antipsychotic drugs on stereotyped behavior.

Subject B This 40-year-old man resided in a

public ICF-MR facility in Kansas. He weighed 112 lbs, was ambulatory, and could hold and manipulate small objects. He was toilet-regulated, but required assistance with other self-care needs. He was blind and the functional use of his hearing was questionable. He recognized his surroundings by contextual cues and inconsistently responded to a coded communication system (tap on shoulder to stand, circle on back indicating correct performance). He differentiated individuals by smell and touch. Health issues at the time were nasal drainage and a hiatal hernia. He had no history of seizures. Before and during the study, he received a multivitamin and Zantac for the hernia.

MRDD RESEARCH REVIEWS CLINICAL TRIALS OF D1 A N D Dz SCHROEDER ET AL. 125

Table 1. Average Hourly Frequency of Self-Injury (SIB), Aggression (Ag), and Face Rubbing (FR), and Weekly Aberrant

Behavior Checklist (ABC) Ratings for Subject B ~~

ABC Ratings

Hyper- Stereo- Leth- Irnt-

Hourly Frequency

Drug Phase SIB Ag FR amvity typy argy ability

Baseline 148 14 38 22 4 8 8 Placebo 102 18 73 22 6 8 8 Clozapine

100 mg 81 12 64 9 2 1 4 200 mg 46 1 56 0 0 0 2 300 mg 18 0 26 0 0 0 2 200 mg 23 0 64 1 0 0 3 225 mg 21 1 39 1 2 0 2 Clozapine 24 1 38 1 0 0 1

225 iiig 14 1 21 2 1 2 2

and Valproic Acid, 200 mg

Clozapine and Valproic Acid

This man had been institutionalized at the age of six years with a diagnosis of profound mental retardation associated with premature birth. He had an early history of chronic self-injury and aggression. He had numerous bruised and scarred areas on his head and face from previous self-injury. As a protective measure, he wore a soft helmet.

This participant was chosen because of the refractory nature of his self-injury. Previous behavioral interventions involving both restrictive and non- restrictive interventions had not been particularly effective. Functional assessments using analog sessions [Iwata et al., 19821 to determine the primary function of self-injury yielded slightly higher rates of SIB in Alone and Escape conditions, suggesting the possibility that some SIB was maintained by sensory consequences and contingent escape from or postpone- ment of instructional sessions. Treat- ments designed to provide alternate sensory consequences and to teach basic communication skills in the form of a response that allowed escape had been generally unsuccessful. A program designed to develop a response incompatible with self-injury was somewhat suc- cesshl because the participant would hold and manipulate a plastic soda bottle for extended periods. Numerous trials with a variety of psychotropic medications, including neuroleptics, had been unsuccessful.

Three behaviors were targeted for observation. One was SIB including hitting himself with any amount of force on the face, forehead, or head. He generally hit himself with a closed fist or

126

palm, but sometimes used objects such as a plastic pop bottle that he often held. All topographies, including strikes when the subject was wearing his protective helmet, were counted. Physical aggression, the second behavior, included hits, kicks, head-butts, and gum bites (participant is edentulous) to another person, even if the blows were blocked by staff. The third behavior, face rubbing, was defined as rubbing his face with his fingers or palm. Discrete behaviors were counted each time the subject’s hand dropped below his shoulder level.

Our study of Subject B employed a 17-week double-blind crossover design similar to Subject A’s trial, after which the staff made the clinical decision to raise the dose higher than 100 ing per day. Two measures, the MABS and the scatter plot, were not used. The subject was observed for two weeks in baseline conditions of no drug administration. The staff and observers did not know when the drug trials actually began and throughout the study were never informed of the dosage levels. Weekly blood samples were drawn begnning during the placebo sessions, which continued for four weeks. The length of the placebo trial was determined by random selection, with two, three, four, or five weeks as possible options.

In the seventh week, clozapine was administered beginning with a dose of 10 mg per day, which was gradually increased in 10-mg increments across the next 10 weeks until a daily dose of 100 mg was reached. That daily dose was maintained for five weeks. In week 21, dosage increases of 10 mg a week

commenced until the dosage reached 200 mg daily, which was maintained for ten weeks. In week 40, the dose was again titrated upward at a rate of 25 mg for four weeks until his maximum daily dose of 300 mg was reached. That regimen was continued for four weeks. During week 46, at a daily dosage of 300 mg, the subject had a seizure. Consequently, the clozapine was reduced to 250 mg and within 5 weeks, to 200 mg. At week 56, in response to increased SIB, the clozapine dose was again titrated upward to 210 mg, then to 225 mg. Seizures continued, however, so the dosage was again reduced to 200 mg in week 68. At this point, valproic acid (Depakote) (500 mg) was added to control the seizures. Although a therapeutic blood level was established for the Depakote and the clozapine dosage was held at 200 mg daily, the frequency of SIB increased. Thus, the dosage of clozapine was increased to 225 mg at week 83. Both drugs remained at these dosages for the remainder of the study. The addition of an anticonvulsant was not preplanned. The decision to use it was based on an interdisciplinary meeting during it was determined that the potential benefits ofa positive clinical response outweighed the side effects.

Table 1 shows the average hourly rates of SIB, aggression, and face rubbing, as well as weekly ABC ratings. The data points were calculated by totaling the frequency of each target behavior for the week and dividing that by the number of hourly sessions. There was a gradual but dramatic reduction in the frequency of SIB and physical aggression. Visual analysis suggests that these reductions were related to increases in the dosage of clozapine. By week 30, at a dose of 200 mg, the frequency of physically aggressive behavior was reduced to near zero. There was a corresponding ten-fold reduction in the rate of SIB by week 46 at 300 mg. The staff ratings also agreed with the videotaped observations. At present, this subject is still being given clozapine with little sedation and few side effects. The frequency of his face rubbing appeared to be unaffected by clozapine. The subject’s sleep patterns also improved, with an increase from 3.5 hours to 7.0 hours of sleep per night.

Subject C This 43-year-old woman, 5 feet 1

inches tall and weighing 101 pounds, was ambulatory but walked with kyphotic (humped) posture. She was considered mildly quadriplegic and had pronated feet that required custom-molded shoes. Her

MRDD RESEARCH &VIEWS CLINICAL TRIALS OF D1 AND DZ SCHROEDER ETAL.

hearing was considered to be within normal limits and her vision was functional but astigmatic. Health issues included hypothyroidism and a history of seizures, for which, during the entire study, she received synthroid and valproic acid. Her self-care skills were limited. She was capable of feedmg herself with a spoon when assisted, but often refused to do so. She could remove some articles of clothing but did not dress herself. She was successfully toileted on a schedule and occasionally indicated to staff that she had to use the bathroom. However, her communication was rudi- mentary. She occasionally said a few words out of context, but made her needs known with body language, gestures, and facial expressions.

The woman had been institutionalized at the age of 13 years with a diagnosis of profound mental retardation due to unspecified conditions. She had a history of self-injury that reportedly to started when she was age 4. Because of facial bruising and lacerations, she wore protective arm splints during the most of her waking hours. She was considered clinically appropriate for clozapine, primarily because of the refractory nature of her self-injury. She had responded poorly to a variety of pharmacological and behavioral treatments. A brief history of her treatments included an unspecified conditioning technique for self-stirnulatory chin hitting, the use of padded mittens, and differential reinforcement of other behaviors, which caused “no consistent change.” A differential reinforcement of incompatible behavior during prevoca- tional activities was reported to have resulted in her participation in 40% of tasks without SIB but appeared to be ineffective due to continued injury and fluctuations in rates. An individual program involving blocking and redirection to ongoing activities, along with overcor- rection procedure and restraint, were also considered to have failed. Several trials with neuroleptics alone and in combination with lithium, inderal, and buspar were attempted with no success. More recent attempts at treatment based on functional analysis had also been ineffective. In general, this woman’s self-injury appeared to be generalized to a variety of stimulus conditions and consequences, including escape from demands, attention, communication, and sensory stimu- lation.

Self-injury was the primary behavior targeted for observation. Her SIB was defined as hitting, bangng, or attempting to hit or bang any part of her body. According to the study protocol, the

Table 2. Average Frequency of Self-Injury (SIB) in Leisure and Demand Settings and Weekly Aberrant Behavior Checklist (ABC)

Ratings for Subject C ~

SIB Frequency ABC Ratings

Leisure Demand Hyper Stereo- Leth- Irrit- Drug Phate Setting Setting activity typy a r u ability

Baseline 39 50 25 9 23 16 Placebo 48 52 10 6 26 6 Titration to 48 41 11 7 30 7

Steady State 9 41 8 6 24 8

Titration 21 53 8 6 20 11

Steady State 15 46 12 7 21 14

Baseline 44 77 9 6 11 10

300 mg

at 300 mg

to 475 mg

at 300 mg

subject was to be videotaped for a minimum of one hour during a structured demand setting and one hour of free leisure time each week. During the structured demand situations she was placed in a one-on-one situation and required to participate in a variety of simple tasks such as handing her trainer an object. During leisure time she was gwen free access to her living room and bedroom, where a variety of leisure materials were available. Staff were in- structed to interact with her briefly on the average of at least every 5 minutes, but to leave her free to do as she pleased. In addition to videotaping, the protocol called for weekly rating scales to be completed as specified for Subjects A and B.

Instructions to the observer during viewing of the weekly videotapes were the same as with Subject B. The observer used a 10-second interval system to record data, which were plotted in terms of the percentage of intervals during which self-injury was observed. Reliabil- ity was assessed as least twice each month, when the primary observer and a second trained observer viewed and scored a randomly selected film, with both observers using the same recording procedures as were used with the first subject. Interval-by-interval agreement was calculated by frequency of occurrence and nonoccurrence by dividing the number of intervals during which both observers agreed that self-injury had or had not occurred by the total number of intervals, then multiplying by 100. Reliability percentages ranged from 93 to loo%, with a mean of 95% for all intervals calculated.

Subject C was not part of the IND protocol because she had had seizures,

MRDD RESEARCH REVIEWS CLINICAL TRIALS OF D1 A N D D2 SCHROEDER ET AL.

which were currently controlled by valproic acid and was receiving mesoridazine (104 mg per day) for SIB. Neverthe- less, the staff at this facility have adopted a similar protocol as standard clinical procedure. Being very concerned about the potential for tardive dyskinesia related to mesoridazine and about the subject’s intractable SIB, they decided to do a 73-week open trial of clozapine. The subject was observed for eight weeks in baseline conditions, then two weeks in placebo conditions before drug titration began.

Weekly drug titrations occurred over 14 weeks, during which clozapine was begun at 25 mg per day and increased in 25-mg increments to 300 mg. During the same period, the dosage of mesoridazine was decreased from 105 mg per day in 10-mg weekly decrements to 0. Titration was followed by 14 weeks during which the subject was given 300 mg per day of clozapine only. Because an optimum therapeutic response had not occurred, the clozapine dosage was then titrated up to 475 mg per day over a seven-week period. Then, when the subject’s SIB worsened, the clozapine was again reduced to 300 mg for seven weeks. At that point, the treatment team decided to discontinue the use of clozapine. N o seizures or extrapyramidal side effects had occurred during administration of the drug, although some other side effects, including occasional vomiting, drowsi- ness, agtation, weight gain, and increased urinary frequency did occur. These side effects all decreased as the dosage stabi- lized.

The main results can be seen in Table 2. A nearly five-fold decrease in SIB in the leisure setting was related to clozapine (300 mg) but did not occur in

127

the demand setting. This behavioral sypersensitivity was also noted by Schroeder and Gualtieri [1985] upon thioridazine withdrawal. Although this effect could have been partially the result of the withdrawal of mesoridazine, baseline follow-up suggested that the effect was due to clozapine. The ABC ratings showed that the effect of clozapine was not due to changes in the subject's degree of lethargy or irritability. In any case, the size of the effect was judged by the treatment team as not clinically significant enough to continue the clozapine trial, and it was stopped.

SUMMARY AND CONCLUSIONS

The clinical trials of clozapine for SIB have been limited, but they offer signs of encouragement. A few reports of patients dually diagnosed as having refractory schizophrenia or organic mood disorders together with mild mental retardation, aggression, and occasional SIB have shown positive responses. We are aware of more than 100 unpublished cases [Rubin, 19951 in which similar claims have been made. However, less is known about the responses of individuals with refractory SIB and severe or profound mental retardation. W e had one dramatic responder, one nonresponder, and one partial responder to clozapine. At this point, it appears that a large controlled study of clozapine for SIB, with particular attention to inclusion criteria of subjects, proper functional assessments, and clinical and ecological validity, is warranted.

As we learn more about the complex behavioral and b i o l o g d dynamics of SIB, an overriding question remains. Why do people select this particular form of apparently counter- intuitive behavior to express themselves? The answer has eluded a host of theoreti- cians with a variety of behavioral or biologcal hypotheses. If knowledge of the causes and treatment of SIB is to advance, there must be, as the papers in this issue show, a multifaceted approach that reconciles all known facts about both its behavioral and biological antecedants.

If we believe that SIB is the result of a faulty neural network, then defining the genetic, neurochemical, and neuro- anatomical risk factors that affect susceptibility will allow a better understanding of the etiology of SIB. Exploring the neurochemical transmission dynamics of SIB at each level of the neural network should provide clues to its overall functioning.

A key function in the overall neural network for SIB appears to be the faulty development of D, -dopamine receptors in the nigrostriatal pathways. This conclu- sion is supported by the neonatal 6-OHDA dopamine depletion model in rats, 6-OHDA lesions in the ventralmedial tegmentum of the brainstem of monkeys, as well as corroborative clinical trials of D, and D2-dopamine modulating drugs in humans with SIB and mental retardation. This work is in its infancy, however. What role the D,-dopamine system shares with its partners-the opioid peptide system, serotonergic systems, adrenergic systems, GABAergic systems, and adenosine-to produce SIB still remains to be explored. Such forums as the present one give us an exciting glimpse of our future understanding of SIB.

ACKNOWLEDGMENTS This study and preparation of the

manuscript were supported by NICHD grants 02528,26927, and 23042.

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