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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Adv Neurodev Disord. 2020 May 20;4(3):247–252. doi: 10.1007/s41252-020-00158-7

Changes in Stereotypical Behavior Following Chlorpromazine Termination: Polypharmcy Effects on Response Class Membership

Maria G Valdovinos 1, Marisela Aguilar 1, Drew Piersma 1, Alyssa Wilkinson 1, Craig H Kennedy 2
PMCID: PMC7962922  NIHMSID: NIHMS1596184  PMID: 33738335

Abstract

Objectives:

A paucity of information exists relating to the possible biological and environmental interactions influencing the occurrence of stereotypical behavior. In particular, there is limited research on the effects of psychotropic medication use on stereotypy presentation in individuals diagnosed with developmental disabilities such as intellectual disability and autism spectrum disorder.

Methods:

We studied the stereotypy of a man with autism spectrum disorder and intellectual disability across 2 years. The topographies of stereotypical behavior included walking in circles, head tapping, arm flinging, and object stereotypy. These behaviors were observed weekly while the participant received daily dosages of 25 mg of chlorpromazine, 1.5 mg of lorazepam, and 2,500 mg of divalproex. At Week 75, chlorpromazine was discontinued while the other drugs and dosages were maintained.

Results:

We observed a statistically significant decrease in walking in circles, but no changes in the other topographies of stereotypy.

Conclusions:

The results suggest that the gross motor activity was differentially affected by the chlorpromazine discontinuation and also suggests that alterations in dopamine receptor binding may have selectively influenced changes in stereotypical responding.

Keywords: stereotypy, autism spectrum disorder, intellectual disability, chlorpromazine, psychotropic medication, behavior change

Stereotypic behavior describes a group of actions that are invariant, repetitive and restricted in nature (e.g., Cunningham and Schreibman 2008; Schroeder 1970). Topographies of stereotypy may include repetitive motor actions, such as body rocking and hand flapping or more complex behaviors, such as fixation on specific objects or gross motor rituals (Luiselli et al. 2004; Melo et al. 2019). Additionally, stereotypy can also present as vocalizations such as repetitive sounds and echolalia (van Haaren 2015). Although neurotypical individuals may engage in stereotypy, these behaviors are a defining characteristic in autism spectrum disorder (ASD) and intellectual disability (ID; Rumsey et al. 1985).

The causes of stereotypy are believed to be a complex interaction of biological and environmental factors (Schroeder et al. 2002). Biological factors can include altered neurotransmitter systems and brain circuitry (Bos et al. 2010). For example, stereotypy has been linked to altered dopaminergic activity within the basal ganglia (Staal 2015). Additionally, complex motor stereotypy has been hypothesized to be associated with decreased levels of GABA in the anterior cingulate cortex and striatum (Péter et al. 2017). An associated trend stemming from the emerging neurobiological understanding of stereotypy, is mental health practitioner’s use of various psychotropic medications to reduce the frequency of stereotypical responding (Valdovinos et al. 2005). In fact, polypharmacy, or the use of multiple medication types, has become very common among people with ASD/ID (Esbensen et al. 2009) although there is inconsistent evidence regarding the effectiveness of polypharmacy for the treatment of challenging behavior of individuals with ASD and ID (de Kuijper et al. 2014; Sheehan and Hassiotis 2017). That notwithstanding, this increasing trend in polypharmacy has also extended to the treatment of stereotypy (Bowring et al., 2017), despite the fact that much is still unknown about the mechanism(s) of action of various drugs on stereotypical responding.

Even though there is evidence to support biological influences on the presentation of stereotypy, environmental variables also influence stereotypical responding. Behavioral analyses of stereotypy often find sensory reinforcement - also referred to as automatic reinforcement - as a maintaining cause of these behaviors (Kennedy and May in press; Rapp and Vollmer 2005). In other words, the stereotypical behaviors emitted by a person with ASD and/or ID occur to produce or reduce stimulation in the individual’s environment. Such behaviors tend to be persistent and invariant over time with topographies and rates of behavior remaining the same from childhood into adulthood (Hustyi et al. 2014). Over the past decade there has been an emerging awareness that stereotypical behaviors can have multiple topological forms, but can function as members of the same response class (Kennedy et al., 2000). That is, although an individual may emit various types of stereotypy, each of these behaviors may serve a similar operant function and thus be functionally substitutable in terms of its effect on the environment.

Little is known about possible biological and environmental interactions on the occurrence and persistence of stereotypy, particularly in terms of polypharmacy and response class membership. In this case report we studied the occurrence of a group of stereotypic behaviors (i.e., a response class) in a man with ASD and ID that occurred at consistent rates over many months of observation. However, when an alteration in the participant’s polypharmacy psychotropic regimen was made (i.e., chlorpromazine was terminated), one member of the response class showed sensitivity to the pharmacological change while other forms of stereotypy remained unchanged.

Method

Participant

The participant took part in a larger three-year research project investigating the impact of psychotropic medication changes on aggressive and self-injurious behavior (see Valdovinos et al. 2016). Garrett was a 42-year old, Caucasian male diagnosed with ASD, generalized anxiety disorder, ID, and insomnia.

Procedures

Experimental Design.

We used a descriptive, longitudinal approach within this case study.

Setting.

Garrett lived in a home within the community along with three other housemates and had 24 hr direct-care staff support. He was observed in his home for 1 hr each week on the same day at approximately the same time (with exception of holidays and University breaks) across a period of 30 months for a total of 103 weekly observations.

Target Behaviors.

Garrett engaged in four different stereotypic behaviors: Walking in circles, head tapping, arm flinging, and stereotypy with objects. Walking in circles was defined as walking in a circle with a diameter approximately smaller than his arm span or within one room. Head tapping was operationally defined as raising his hand to the head or face area and making light, short contact two or more times, or rubbing his hand on his hair back and forth repeatedly. Arm flinging was defined as the sudden, violent flinging of the arms without tension in his hands. Stereotypy with objects was defined as tearing papers, shaking containers of liquid, or pouring multiple cups of water down the sink. In previous functional behavioral assessments (Valdovinos et al. 2016), Garrett’s stereotypy was not identified as being influenced by social reinforcers (e.g., attention or demand) and instead seemed to be a function of nonsocial or automatic reinforcement (see Kennedy 2000).

Observers and Observer Training.

Each of the stereotypies was recorded and scored by trained observers using a continuous, timed-event sampling procedure within The Observer® XT software (Noldus). Observers were trained to code behavior using The Observer® XT software on sample observations. When observers achieved 80% agreement or higher on three consecutive observations, they began scoring participant data.

Medication Changes.

At the onset of the study, Garrett was taking 25 mg of chlorpromazine (Thorazine), 1.5 mg of lorazepam (Ativan), and 2,500 mg of divalproex (Depakote) on a daily basis. Chlorpromazine was discontinued following Observation 75 while dosages of lorazepam and divalproex were maintained. The medication changes occurred independent from the research and were based on information provided to the physician by agency staff regarding challenging behaviors observed by direct-care staff.

Interobserver agreement.

Interobserver agreement (IOA) was calculated for 33% of observations. Point-by-point agreement was calculated using a window of three seconds and IOA percentages were calculated by dividing the number of agreements by the total sum of agreements and disagreements and then multiplying by 100% (Kennedy 2005). Mean IOA for walking in circles was 83.8% (range, 70.2% to 100%), 82.1% for head tapping (range, 42.1% to 100%), 92.4% for arm flinging (range, 78% to 100%), and 97.3% for stereotypy with objects (range, 73.2% to 100%).

Data Analysis

Frequency per hr for each topography of stereotypy was compared prior to and after the discontinuation of chlorpromazine using independent samples t-tests (two tailed).

Results

Figure 1 shows the occurrence per hr of Garrett’s stereotypy. The behaviors are presented as walking in circles (closed circles) versus arm flinging, head tapping, and object manipulation (open circles) and weekly observation data are grouped by 15. The latter behaviors (open circles) occurred at a mean frequency per hr of 0.56 (range, 0.01 to 3.14) in baseline and 0.65 (range, 0.13 to 2.31) following termination of chlorpromazine (these data are also grouped by 15 with the exception of a final grouping of 13). Arm flinging, head tapping, and object manipulation did not appear to change following discontinuation of chlorpromazine. However, the frequency of walking in circles (closed circles) decreased following termination of chlorpromazine. Walking in circles occurred at a mean frequency per hr of 1.22 (range, 0.11 to 3.8) in baseline and 0.84 (range, 0.18 to 2.02) following termination of chlorpromazine.

Figure 1.

Figure 1.

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Graph shows the mean rate of stereotypy per hr of stereotypy for Garrett. One observation was made per wk and are summarized in blocks of 15 observations. The closed circles represent occurrences of walking in circles, while the open circles represent occurrences of arm flinging, head tapping, and object manipulation. Chlorpromazine discontinuation is noted by the doted vertical line.

Figure 2 shows each topography of stereotypy during baseline and following chlorpromazine termination. Baseline means (SDs) for arm flinging, head tapping, object manipulation and walking in circles were 0.52 (SD = 0.49), 0.23 (SD = 0.16), 0.04 (SD = 0.05), and 1.22 (SD = 0.69), respectively. Means (SDs) following chlorpromazine discontinuation for arm flinging, head tapping, object manipulation, and walking in circles were 0.61 (SD = 0.5), 0.2 (SD = 0.17), 0.04 (SD = 0.04), and 0.84 (SD = 0.56), respectively. We conducted pre-/post t-test comparisons for before and after chlorpromazine discontinuation and found no statistically significant changes for arm flinging (t = −0.88, df = 51, p < .38, ns), head tapping (t = 0.89, df = 49, p < .40, ns), or object manipulation (t = 0.56, df = 59, p < .58, ns). However, there was a significant decrease in the frequency of walking in circles before and after chlorpromazine discontinuation (t = 2.89, df = 63, p < .005).

Figure 2.

Figure 2.

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The mean rate per hr of stereotypy for Garrett. Light bars and dark bars, respectively, represent the rate of occurrence of stereotypical topographies prior to, or following, the termination of chlorpromazine. The asterisk indicates a significant difference at the p < .005 level for walking in circles.

Discussion

Individuals with ASD and ID commonly engage in repetitive and stereotypical behaviors, the causes of which are only partially understood. The current study evaluated four topographies of stereotypy (i.e., arm flinging, head tapping, object manipulation, and walking in circles) for one individual over 2 years of weekly naturalistic observation. During the initial observation period (75 weeks), which included daily dosages of chlorpromazine, lorazepam, and divalproex, all four stereotypical behaviors showed a consistent pattern of occurrence. When the participant’s chlorpromazine was discontinued, the stereotypical behaviors differentiated into a cluster of three behaviors that were unchanged in occurrence (i.e., arm flinging, head tapping, object manipulation) and one which significantly decreased in frequency (i.e., walking in circles). These findings suggest that the elimination of chlorpromazine differentially affected the topographies of stereotypy with only gross-motor responding being the focus of behavior change.

Chlorpromazine is a first-generation antipsychotic that primarily affects dopaminergic systems with a specific affinity for D2 receptors (Boyd-Kimball et al. 2019). Given the activation at these receptor sites, chlorpromazine is known for producing extrapyramidal side effects such as tardive dyskinesia and akathisia. The interaction observed in this study between the discontinuation of chlorpromazine and the decrease of walking in circles, suggests that some topographies of stereotypy may be exacerbated by altered dopaminergic activity as induced by psychotropic medication.

Dysregulated dopaminergic activity within the striatum, which includes the caudate nucleus, is thought to be one contributor to the development of stereotypy in ASD (Péter et al. 2017). Another identified potential contributor to stereotypy is abnormalities of the GABA-ergic system, particularly throughout the striatal region. In an evaluation of upper extremity stereotypy, Harris et al. (2016) found that decreases in GABA levels were associated with increased engagement in stereotypy. Thus, it is plausible that the discontinuation of chlorpromazine could impact gross-motor stereotypy associated with dopaminergic dysregulation, given the innervation of D2 receptors within the striatum, while other topographies would remain unaffected. In terms of response class membership, this suggests that although the various topographies of stereotypy observed in this study were functionally similar, one member of the response class (i.e., walking in circles) was differentially sensitive to chlorpromazine.

Limitations and Future Research Directions

The present study characterized the effects changes in psychotropic medication had on an individual diagnosed with ASD and ID. Although this case provides insight into the effects, these effects cannot be generalized to a larger population and additional research to extend the generality of these findings is warranted. Additionally, it is possible that other factors might explain the increases and decreases observed over time. For example, the highest rates of walking in circles tended to occur during spring and summer months versus the lower rates during winter months, although not exclusively. Thus, temperature or opportunity to be outside versus inside may have influenced engagement in this behavior. Also, since we did not assess the clinical or social validity of the behavior change, we should note that the changes in the gross motor stereotypy may have only been statistically significant, but not socially meaningful.

Future research should evaluate how extrapyramidal side effects present in those with ASD who also engage in gross motor stereotypies. Perhaps baseline measures of stereotypy should be conducted prior to the initiation of any medication known to target the dopaminergic system as a way to identify and distinguish between worsening stereotypy and development of antipsychotic movement-related disorders. That notwithstanding, this study illustrates that other forms of stereotypy appear to remain fairly consistent in presentation over time and medication changes. Research has recently begun to examine the success with which individuals with developmental disabilities can be taken off of long-term antipsychotic medication (de Kuijper et al., 2014; Sheehan and Hassiotis, 2017). Additional work should be conducted to evaluate the effects discontinuation or deprescribing of psychotropic medications (e.g., other antipsychotics, antidepressants, anxiolytics) has on behavior (i.e., stereotypical, adaptive, challenging) of those with ASD and ID.

Acknowledgements

We would like to thank Annette Hass, Meara Henninger-McMahon, Lisa Beard, Sara Hillring, Haley Seibert, Gabrielle Griffith, and Bailey Boyle for their assistance in this project. Alyssa Wilkinson is now at the Nelson County Public School System. Drew Piersma is now in the Department of Behavioral Psychology at Kennedy Krieger Institute. Sara Hillring is now in the Department of Nutrition and Integrative Physiology at the University of Utah.

Funding: This research was funded by National Institute of Child Health and Human Development grant 1R15HD072497-01.

Footnotes

Publisher's Disclaimer: This Author Accepted Manuscript is a PDF file of a an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethics Declarations

Ethics Statement

Ethical approval of the study was obtained from the Institutional Review Board of Drake University. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent Statement

Informed consent was obtained from all individual participants included in the study.

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