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Tardive dyskinesia associated with metoclopramide in persons with developmental disabilities
Research in Developmental Disabilities 23 (2002) 224±233
Tardive dyskinesia associated with metoclopramide in persons with developmental disabilities Johnny L. Matsona,*, Erik A. Mayvillea, JoAnne Bieleckia, Yemonja Smallsa, C. Scott Eckholdtb a
Department of Psychology, Louisiana State University, 236 Audubon Hall, Baton Rouge, LA 70803, USA b Pinecrest Developmental Center, Pineville, LA, USA Received 4 January 2002; accepted 12 February 2002
Abstract Metoclopramide is an anti-emetic medication that has been associated with movement disorders such as extra-pyramidal reactions and tardive dyskinesia (TD). Reports of these reactions have been documented in the general population, but investigations of side effects in persons with mental retardation are scant. Given the high incidence of gastrointestinal disturbance in persons with mental retardation, and the popularity of this medication to treat such problems, these individuals could be at risk for developing movement disorders resulting from metoclopramide use. We compared incidence rates of TD over a 1-year period in developmentally disabled individuals taking either metoclopramide, typical antipsychotics, or no psychotropic medications (Table 1). Assessment was completed using the Dyskinesia Identi®cation SystemÐCondensed User Scale (DISCUS), a standardized measure of TD found to be reliable and valid for persons with mental retardation. No signi®cant differences in DISCUS scores between the metoclopramide and antipsychotic treated groups were noted across four measurements taken during the course of 1 year. Additionally, no difference was found between these two groups for a number of participants who met criteria for probable TD on at least one of the DISCUS administrations. Comparisons between all three groups on one testing occasion revealed a signi®cant difference between groups. The no psychotropic control group showed signi®cantly less TD symptomology than the antipsychotic or metoclopramide groups. # 2002 Published by Elsevier Science Ltd. Keywords: tardive dyskinesia; metoclopramide; mental retardation *
Corresponding author. Tel.: 1-225-388-4104. E-mail address: [email protected] (J.L. Matson).
0891-4222/02/$ ± see front matter # 2002 Published by Elsevier Science Ltd. PII: S 0 8 9 1 - 4 2 2 2 ( 0 2 ) 0 0 1 0 0 - 2
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Table 1 Demographic and Axis I information for metoclopramide, typical antipsychotics, and no psychotropic medication groups Metoclopramide Group (N 25) Axis I diagnosis Bipolar Disorder Schizophrenia Autism/PDD Anxiety Disorder NOS Pica Stereotypic Movement Disorder Stereotypic Movement Disorder with SIB Impulse Control Disorder NOS Intermittent Explosive Disorder Rumination No diagnosis
Typical Antipsychotic Group (N 25)
No Psychotropic Medication Group (N 25)
1 0 2 0 0 3 4
1 3 5 1 1 2 9
0 0 3 0 0 2 0
0 0 0 16
4 1 0 2
0 0 1 19
1. Introduction Antipsychotic medications have long been used to treat psychiatric disturbance and behavioral excesses in a variety of populations. While these medications are mainstays in the control of psychotic behavior, a host of deleterious side effects that often accompany the use of these medications has been well documented. Tardive dyskinesia (TD), a movement disorder characterized by frequent, repetitive, involuntary movements of the lips, tongue, jaw, face, trunk, and/or limbs, is one of the most notorious side effects of antipsychotic medications and has been found to affect approximately 24% of the general psychiatric patients taking antipsychotic medication (Jeste & Caligiuri, 1993; Wilson, Lott, & Tsai, 1998). The risk of developing this condition increases with length of treatment, a disturbing ®nding given the often chronic use of these medications (Jeste & Caligiuri, 1993). Less is known about TD in persons with mental retardation. Several characteristics of TD are similar for general psychiatric and developmentally disabled populations (Cohen, Khan, Zheng, & Chiles, 1991). Prevalence estimates in persons with mental retardation taking antipsychotic medication range from 17 to 36%, while a rate of 24% has been found in the general psychiatric population (Cohen et al., 1991; Jeste & Caligiuri, 1993). Additionally, some of the same risk factors have been identi®ed for this population (e.g., increasing age, female gender, lower cognitive functioning), although some studies have yielded con¯icting ®ndings (Matson, Bamburg, Mayville, & Logan, 2000; Richardson, Hlaugland, Pass, & Craig, 1986; Youseff & Waddington, 1988). Dopamine antagonism is the most widely cited mechanism of action responsible for the therapeutic and side effects of antipsychotic medications, though multiple neurotransmitter systems are affected (McKim, 1996). A number of
226
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dopamine-antagonizing medications also have well-documented utility in the control of centrally induced gastrointestinal disturbance, and are given to a variety of patient populations for this purpose (Fernando & Eisendrath, 1991). Metoclopramide is a dopaminergic antagonist that is rarely used for psychiatric purposes, but is an anti-emetic thought to control nausea and vomiting through dopamine antagonism in the chemoreceptor trigger zone in the medulla oblongata (Gralla et al., 1981). As with many medications with antidopaminergic properties, metoclopramide has been associated with the same adverse motor side effects demonstrated by antipsychotic medications, including dystonia (Grimes, Hassan, & Preston, 1982), akathisia (Granzini, Casey, Hoffman, & McCall, 1993), and TD (Granzini et al., 1993; Miller & Jankovic, 1989; Sewell & Jeste, 1992; Sewell, Kodsi, Caligiuri & Jeste, 1994; Wilholm, Mortimer, Boethius, & Haggstrom, 1984). In a review of the literature on metoclopramide-induced TD, Sewell and Jeste (1992) found 67 case reports in which this medication was implicated in TD development. Although there is less awareness of the risk of such side effects with metoclopramide use, the existing literature in the general population reports that side effects are not uncommon (Jeste & Caligiuri, 1993). To date, no studies investigating the incidence of TD in persons with mental retardation taking metoclopramide have been conducted. Given the high incidence of gastrointestinal disturbance in persons with mental retardation and the popularity of this medication to treat such problems, mentally retarded individuals taking this medication could be at risk for developing metoclopramide-induced movement disorders. We examined the incidence of TD in 25 persons with mental retardation who were taking metoclopramide. We compared scores on a standardized measure of TD of these individuals with 25 individuals with mental retardation who were taking typical antipsychotic medications, and with a third group of mentally retarded individuals who were not taking metoclopramide or psychotropic medication. Participants were matched on age, sex, and severity of mental retardation. Analyses were conducted to identify differences in incidence of TD between the two groups, as well as the course of TD in both groups over a 1-year time period. 2. Method 2.1. Participants We obtained information on 75 adults with mental retardation, all of whom resided at Pinecrest Developmental Center in Pineville, LA. Individuals were assigned to one of three groups (N 25 in each case) depending on type of medication administered: (a) metoclopramide; (b) typical antipsychotics (thioridazine, chlorpromazine or haloperidol); or (c) no metoclopramide or psychotropic medication. Where possible, we matched the groups on an individual basis for three factors: (a) age, (b) sex, and (c) level of mental retardation. In addition, we obtained information from medical records regarding (a) Axis I diagnoses and (b) other psychotropic medications for each participant.
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A number of participants had received a variety of Axis I diagnoses, including Autism or Pervasive Developmental Disorder (N 10), Bipolar Disorder (N 2), Impulse Control Disorder (N 4), Schizophrenia (N 3), Intermittent Explosive Disorder (N 1), Pica (N 1), and Stereotypic Movement Disorder with Self-Injurious Behavior (SIB) (N 13) and without SIB (7). Thirty-®ve participants did not have an Axis I diagnosis, the majority of which were in the metoclopramide (N 16) and no psychotropic medication groups (N 19). Participants were matched for the variables of age (mean age of 39 in metoclopramide, 41 in typical antipsychotic group, and 40 in no psychotropic group), gender (9 males, 16 females in the metoclopramide group, 10 males and 15 females in both the typical antipsychotic and no psychotropic groups), and level of mental retardation (3 severe and 22 profound in the metoclopromide group; 3 moderate, 5 severe, and 17 profound in typical antipsychotic group; and 1 mild, 5 moderate, 5 severe, and 14 profound in the no psychotropic group). Regarding medication dose, participants in the metoclopramide group averaged 33 mg per day, and participants in the typical antipsychotic group averaged 211 mg per day (CPZ equiv. dose); doses of medication for both groups remained stable throughout the study with the exception of three participants in the metoclopramide group (each had one 10 mg per day reduction) and ®ve participants in the antipsychotic group (each had a CPZ equivalent of 100 mg per day reduction). Five participants in the metoclopramide group were taking concurrent psychotropic medications, all of whom were taking only one psychotropic. Types of psychotropic medications included mood stabilizers (N 3), antidepressants (N 1) and beta blockers (N 1). Other relevant concurrent medications taken in this group included anti-convulsants (N 19) and antihistamines (N 1). Ten individuals in the typical antipsychotic medication group were taking concurrent psychotropic medications (9 taking a total of two psychotropics, 1 taking three psychotropics), including mood stabilizers (N 6), anxiolytics (N 2), and anticholinergics (N 1). Other relevant concurrent medications taken in the antipsychotic group included anti-convulsants (N 2) and antihistamines (N 1). Speci®c histories of metoclopramide and typical antipsychotic medication use was not obtained due to availability of medication history records for 4 previous years only. However, available records con®rmed that participants in the metoclopramide group did not have a history of exposure to any other dopamine blocking agents. Additionally, records revealed that participants in the metoclopramide and typical antipsychotic groups had received their respective medications for at least 4 years, and participants in the no psychotropic medication control group had never received an antipsychotic or metoclopramide. 2.2. Instruments Participants were evaluated with the DISCUS, a standardized measure of TD (Sprague & Kalachnik, 1991). The DISCUS is a 15-item rating scale designed to identify dyskinetic movements in seven bodily areas: the face, eyes, oral (jaw,
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lips), lingual (tongue), head, upper limbs, and lower limbs. Each item is a symptom (e.g., blinking, tongue tremor, pill rolling) that is rated on a 5-point severity scale, with a score of 0 indicating the symptom is not present and a score of 4 indicating the symptom is severe. Rankings of 1±4 re¯ect severities of minimal, mild, moderate, and severe, respectively. A total score of 5 or greater indicates probable TD; two consecutive scores of 5 indicate persistent TD. Normative data for persons with mental retardation is available for this scale, and the DISCUS has also proven reliable and valid with this population (Sprague & Kalachnik, 1991). 2.3. Procedure Participants in the metoclopramide and typical antipsychotic groups were evaluated with the DISCUS at 3-month intervals a total of four times as part of a mandated routine quarterly examination for medication side-effects. Thus, this study was a retrospective review as opposed to a prospective study. Because they were not routinely assessed for medication side effects, the no psychotropic medication control group was evaluated with the DISCUS on only one occasion that corresponded to the fourth administration in the other two groups. The DISCUS was administered by one of four trained raters, all of whom were graduate students in a Ph.D. clinical psychology training program and had been employed at the developmental center for at least 1 year. Raters received initial training in DISCUS administration and scoring from viewing the DISCUS training videotape and from individual instruction from a senior Ph.D. student who received DISCUS training from a board-certi®ed psychiatrist. Maintenance training was conducted approximately twice yearly through subsequent showings of the videotape. All raters were pro®cient in distinguishing between TD related abnormal movement and other types of potentially confounding movement, such as stereotypies. All DISCUS were conducted in a quiet setting at the participant's home or training facility; administration and scoring time averaged 7 min per client. 3. Results We conducted several analyses to determine differences among the groups on pertinent variables. First, to determine differences among the metoclopramide and typical antipsychotic groups for total DISCUS scores, we conducted a oneway repeated measures analysis of variance (ANOVA) using DISCUS total score as the dependent variable. A signi®cant main effect for time was found [F 2:76; 132 2:99, p :04] (df and p-value corrected using Huynh±Feldt correction for violation of sphericity assumption). A main effect for group was not found [F 1; 48 :02, p :88], nor was a time by group interaction [F 2:76; 132 :52, p :65]. Trend analyses revealed the presence of negative linear trends for both metoclopramide and typical antipsychotic groups for total DISCUS score [F 1; 48 4:33, p :04]. Mean DISCUS scores for the
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Fig. 1. Mean DISCUS scores by participant group across four administrations. No statistical difference was found among the metoclopramide and typical antipsychotic groups across administrations; however, a signi®cant negative linear trend for both groups' scores was identi®ed [F 1; 48 4:33, p :04]. A signi®cant difference among all three groups was found on the fourth DISCUS administration [F 2; 27 3:51, p :04]. Pairwise comparisons indicated that participants taking typical antipsychotics displayed signi®cantly more overall symptoms of TD than did participants taking no psychotropics; the metoclopramide group did not differ from either of the other two.
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metoclopramide and typical antipsychotic groups across administrations are displayed in Fig. 1. Next, a separate one-way ANOVA using the fourth DISCUS administration as the dependent variable was conducted to detect differences between all three groups. A signi®cant difference was detected for total DISCUS score [F 2; 72 3:51, p :04]. Pairwise comparisons (Tukey HSD test) indicated that participants taking typical antipsychotics displayed signi®cantly more overall symptoms of TD than did participants taking no psychotropics; the metoclopramide group did not differ from either of the other two. To further examine differences in probable presence of TD, differences among groups regarding scores that exceeded the recommended cutoff score of 5 were examined. First, the difference between the two medication groups for number of individuals exceeding the cutoff score of 5 for two consecutive administrations (criteria for persistent TD) was examined. A single dichotomous score was Table 2 Mean score of individual items across administrations and percentage of successful DISCUS item administrations for metoclopramide and typical antipsychotic groups Category and Item
Metoclopramide Group
Typical Antipsychotic Group
Mean
% Assessed
Mean
% Assessed
Face Tics (item 1) Grimaces (item 2)
.07 .20
100 100
.13 .09
100 100
Eyes Blinking (item 3)
.11
100
.06
100
.47 .38
100 100
.57 .45
100 100
.64
92
.22
91
.20 .07 .23
82 76 76
.14 .38 .35
83 78 77
.07 .01
100 100
.07 .01
100 100
Oral Chewing/lip smacking (item 4) Puckering/sucking/thrusting lower lip (item 5) Lingual Tongue thrusting/tongue in cheek (item 6) Tonic tongue (item 7) Tongue tremor (item 8) Athetoid/myokymic lateral tongue (item 9) Head/neck/trunk Retrocollis/torticollis (item 10) Shoulder/hip torsion (item 11) Upper limb Athetoid/myokymic ®nger±wrist±arm (item 12) Pill rolling (item 13)
.04
99
.12
100
.22
99
.23
100
Lower limb Ankle ¯exion/foot tapping (item 14)
.13
98
.06
85
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derived based on whether the recommended TD cutoff score of 5 was exceeded at least twice during the four administrations for the metoclopramide and antipsychotic groups. Chi-square analysis did not reveal a statistically signi®cant difference in TD status among the two groups, w2 1 1:50, p :221. Two individuals in the metoclopramide group met criteria for persistent TD, while ®ve met this criteria in the typical antipsychotic group. Next, a single dichotomous score was derived based on whether the recommended TD cutoff score of 5 was exceeded only once during the four administrations for the metoclopramide and antipsychotic groups, and during the one administration for the no drug controls. Chi-square analyses revealed a statistically signi®cant difference in TD status among the three groups, w2 2 10:71, p :005. Ten individuals in each medication group met criteria for probable TD at least once, while only one individual in the no psychotropic control group exceeded this cutoff. The majority of participants were compliant with the standard DISCUS instructions, which include opening one's mouth, sticking out one's tongue, and removing shoes and socks. However, some participants did not comply with all requests. The percentage of successful administrations for each item as well as item means across administrations are presented in Table 2. 4. Discussion We examined the TD pro®les of persons with developmental disabilities who were receiving either metoclopramide, typical antipsychotics, or no psychotropic medications over a 1-year period. Our analyses showed no signi®cant difference in total DISCUS scores between persons taking either metoclopramide of typical antipsychotic medication, with both groups averaging scores below TD threshold on each assessment occasion. Additionally, an analysis of individuals in each group meeting criteria for persistent TD indicated that while several individuals in each group met criteria for persistent TD, the differences between the groups failed to reach statistical signi®cance. However, comparisons between all three groups for meeting probable TD criteria on at least one occasion indicated that a signi®cantly higher number of participants in both medication groups met criteria for probable TD than participants in a no psychotropic control group. Several points about metoclopramide-induced TD in persons with mental retardation emerged. First, our results are consistent with reports of metoclopramide-induced TD in the general population; that is, like traditional antipsychotic agents, metoclopramide can lead to symptoms of TD in persons with mental retardation. Of 50 participants taking either metoclopramide or typical antipsychotics, 10 (40%) in each group met criteria for probable TD at some point during a year's time, a number signi®cantly higher than matched controls. Second, our ®ndings illustrate that metoclopramide-induced TD, like antipsychotic-induced TD, may vary signi®cantly in severity over time, underscoring the need for repeated assessment in clinical settings (Gardos, Cole, Schniebolk, & Salomon, 1987).
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The overall severity of TD symptoms seen in both the metoclopramide and antipsychotic groups was relatively low, and a general downward trend of scores was observed in both groups across the four assessment periods. The reasons for this are not clear. However, individuals in both groups had been taking their respective medications for a number of years, and it is likely that they received medical attention for TD (e.g., increases or decreases in medication dose). Additionally, the stability of medication dose in both medication groups may have obscured the presence TD, as symptoms may present only when medication is withdrawn (Wilson et al., 1998). Medication dose may have also contributed to low scores; both groups were receiving low to modest average doses of respective medication, with the typical antipsychotic group receiving an average of 211 CPZ equiv. mg per day (standard range is 200±800 mg per day; Baldessarini, 1996). While the role of dose on the development of TD is somewhat unclear (Jeste & Caligiuri, 1993), it is possible that this factor combined with close monitoring of TD symptoms by developmental center staff may account for low total DISCUS scores. The downward trend in scores in both groups is statistically signi®cant, but an inspection of group mean scores reveals that the difference in scores from ®rst administration to last is less than one point. It is possible that some participant noncompliance led to underestimation of some TD symptomatology. As shown in Table 2, some items in the lingual and upper and lower limb areas were not assessed; with the exception of ``toe movement,'' both groups were relatively equal in the number of administrations failing to yield a valid score in these areas. Thus, the possibility exists that the DISCUS scores presented here re¯ect a more conservative estimate, especially given the tendency of TD symptoms to present in the lingual area in persons with mental retardation relative to the general psychiatric population (Cohen et al., 1991). While full compliance on all items would produce the most accurate estimates of TD, this is often dif®cult to achievewith individuals who may not understand experimenter requests. Given that only one item fell below the 75% level (toe movement, 55%) and the majority of DISCUS items were administered with 100% compliance, our testing efforts with this population were viewed as successful. All three groups contained participants who had been diagnosed with a Stereotypic Movement Disorder, the majority of whom were in the typical antipsychotic group. This was of some initial concern given possible confusion of TD symptoms and stereotypic movements. However, the majority of TD symptoms observed were those which would not likely be confused with stereotypic movements (e.g., oral±facial). Hip and shoulder torsion and retrocolis/torticolis, two groups of movements that would have been the most likely to be confused with TD symptoms, were observed to occur very infrequently in our sample. Thus, confusion of these two classes of movements was not likely and not considered to be a threat to the validity of our ®ndings. Future studies of metoclopramide-induced TD in persons with mental retardation are warranted given our results. Examination of a larger number of individuals may elucidate information that have gone undetected in our study due to a low number of subjects. An examination of incidence of TD following
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metoclopramide discontinuation or downward titration in dose would also help clarify the potential for metoclopramide-induced TD to develop in persons with mental retardation. References Baldessarini, R. J. (1996). Drugs and the treatment of psychiatric disorders: Psychosis and anxiety. In J. G. Hardman & L. E. Limbird (Eds.), Goodman and Gilman's: The pharmacological basis of therapeutics (9th ed., pp. 431±459). New York: McGraw-Hill. Cohen, S., Khan, A., Zheng, Y., & Chiles, J. (1991). Tardive dyskinesia in the mentally retarded: Comparison of prevalence, risk factors and topography with a schizophrenic population. Acta Psychiatrica Scandinavica, 83, 234±237. Fernando, S. J., & Eisendrath, S. J. (1991). Adverse neuropsychiatric effects of dopamine antagonist medications: Misdiagnosis in the medical setting. Psychosomatics, 32, 426±432. Gardos, G., Cole, J. O., Schniebolk, S., & Salomon, M. (1987). Comparison of severe and mild tardive dyskinesia: Implications for etiology. Journal of Clinical Psychiatry, 48, 359±362. Gralla, R. J., Itri, L. M., Pisko, S. E., Squilante, A. E., Kelsen, D. P., Braun, D. W., Bordin, L. A., Braun, T. J., & Young, C. W. (1981). Antiemetic efficacy of high-dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. New England Journal of Medicine, 305, 905±909. Granzini, L., Casey, D. E., Hoffman, W. F., & McCall, A. L. (1993). The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Archives of Internal Medicine, 28, 1469±1475. Grimes, J. D., Hassan, M. N., & Preston, D. N. (1982). Adverse neurologic effects of metoclopromide. Canadian Medical Association Journal, 126, 23±25. Jeste, D. V., & Caligiuri, M. P. (1993). Tardive dyskinesia. Schizophrenia Bulletin, 19, 303±314. Matson, J. L., Bamburg, J. W., Mayville, E. A., & Logan, J. R. (2000). Tardive dyskinesia and developmental disabilities: An examination of demographics and topography in persons with dual diagnosis. British Journal of Developmental Disabilities, 46, 117±128. McKim, W. A. (1996). Drugs and behavior: An introduction to behavioral pharmacology (3rd ed.). Upper Saddle River, NJ. Miller, L. G., & Jankovic, J. (1989). Metoclopramide-induced movement disorders: Clinical findings with a review of the literature. Archives of Internal Medicine, 149, 2486±2492. Richardson, M., Haugland, G., Pass, R., & Craig, T. J. (1986). The prevalence of tardive dyskinesia in a mentally retarded population. Psychopharmacology Bulletin, 22, 243±249. Sewell, D. D., & Jeste, D. V. (1992). Metoclopramide-associated tardive dyskinesia: An analysis of 67 cases. Archives of Family Medicine, 1, 271±278. Sewell, D. D., Kodsi, A. B., Caligiuri, M. P., & Jeste, D. V. (1994). Metoclopramide and tardive dyskinesia. Biological Psychiatry, 36, 630±632. Sprague, R. L., & Kalachnik, J. E. (1991). Reliability and a total score cutoff for the Dyskinesia Identification System: Condensed User Scale (DISCUS) with mentally ill and mentally retarded populations. Psychopharmacology Bulletin, 27, 51±58. Youseff, H. A., & Waddington, J. L. (1988). Involuntary orofacial movements in hospitalised patients with mental handicap or epilepsy: Relationship of developmental intellectual deficit and presence or absence of long-term exposure to neuroleptics. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 863±865. Wilholm, B. E., Mortimer, O., Boethius, G., & Haggstrom, J. E. (1984). Tardive dyskinesia associated with metoclopramide. British Medical Journal, 288, 545±547. Wilson, J. G., Lott, R. S., & Tsai, L. (1998). Side effects: Recognition and management. In S. Reiss & M. G. Aman (Eds.), Psychotropic medications and developmental disabilities: The international consensus handbook (pp. 95±114). Columbus, OH: The Ohio State University Nisonger Center.
Tardive dyskinesia associated with metoclopramide in persons with developmental disabilities Johnny L. Matsona,*, Erik A. Mayvillea, JoAnne Bieleckia, Yemonja Smallsa, C. Scott Eckholdtb a
Department of Psychology, Louisiana State University, 236 Audubon Hall, Baton Rouge, LA 70803, USA b Pinecrest Developmental Center, Pineville, LA, USA Received 4 January 2002; accepted 12 February 2002
Abstract Metoclopramide is an anti-emetic medication that has been associated with movement disorders such as extra-pyramidal reactions and tardive dyskinesia (TD). Reports of these reactions have been documented in the general population, but investigations of side effects in persons with mental retardation are scant. Given the high incidence of gastrointestinal disturbance in persons with mental retardation, and the popularity of this medication to treat such problems, these individuals could be at risk for developing movement disorders resulting from metoclopramide use. We compared incidence rates of TD over a 1-year period in developmentally disabled individuals taking either metoclopramide, typical antipsychotics, or no psychotropic medications (Table 1). Assessment was completed using the Dyskinesia Identi®cation SystemÐCondensed User Scale (DISCUS), a standardized measure of TD found to be reliable and valid for persons with mental retardation. No signi®cant differences in DISCUS scores between the metoclopramide and antipsychotic treated groups were noted across four measurements taken during the course of 1 year. Additionally, no difference was found between these two groups for a number of participants who met criteria for probable TD on at least one of the DISCUS administrations. Comparisons between all three groups on one testing occasion revealed a signi®cant difference between groups. The no psychotropic control group showed signi®cantly less TD symptomology than the antipsychotic or metoclopramide groups. # 2002 Published by Elsevier Science Ltd. Keywords: tardive dyskinesia; metoclopramide; mental retardation *
Corresponding author. Tel.: 1-225-388-4104. E-mail address: [email protected] (J.L. Matson).
0891-4222/02/$ ± see front matter # 2002 Published by Elsevier Science Ltd. PII: S 0 8 9 1 - 4 2 2 2 ( 0 2 ) 0 0 1 0 0 - 2
J.L. Matson et al. / Research in Developmental Disabilities 23 (2002) 224±233
225
Table 1 Demographic and Axis I information for metoclopramide, typical antipsychotics, and no psychotropic medication groups Metoclopramide Group (N 25) Axis I diagnosis Bipolar Disorder Schizophrenia Autism/PDD Anxiety Disorder NOS Pica Stereotypic Movement Disorder Stereotypic Movement Disorder with SIB Impulse Control Disorder NOS Intermittent Explosive Disorder Rumination No diagnosis
Typical Antipsychotic Group (N 25)
No Psychotropic Medication Group (N 25)
1 0 2 0 0 3 4
1 3 5 1 1 2 9
0 0 3 0 0 2 0
0 0 0 16
4 1 0 2
0 0 1 19
1. Introduction Antipsychotic medications have long been used to treat psychiatric disturbance and behavioral excesses in a variety of populations. While these medications are mainstays in the control of psychotic behavior, a host of deleterious side effects that often accompany the use of these medications has been well documented. Tardive dyskinesia (TD), a movement disorder characterized by frequent, repetitive, involuntary movements of the lips, tongue, jaw, face, trunk, and/or limbs, is one of the most notorious side effects of antipsychotic medications and has been found to affect approximately 24% of the general psychiatric patients taking antipsychotic medication (Jeste & Caligiuri, 1993; Wilson, Lott, & Tsai, 1998). The risk of developing this condition increases with length of treatment, a disturbing ®nding given the often chronic use of these medications (Jeste & Caligiuri, 1993). Less is known about TD in persons with mental retardation. Several characteristics of TD are similar for general psychiatric and developmentally disabled populations (Cohen, Khan, Zheng, & Chiles, 1991). Prevalence estimates in persons with mental retardation taking antipsychotic medication range from 17 to 36%, while a rate of 24% has been found in the general psychiatric population (Cohen et al., 1991; Jeste & Caligiuri, 1993). Additionally, some of the same risk factors have been identi®ed for this population (e.g., increasing age, female gender, lower cognitive functioning), although some studies have yielded con¯icting ®ndings (Matson, Bamburg, Mayville, & Logan, 2000; Richardson, Hlaugland, Pass, & Craig, 1986; Youseff & Waddington, 1988). Dopamine antagonism is the most widely cited mechanism of action responsible for the therapeutic and side effects of antipsychotic medications, though multiple neurotransmitter systems are affected (McKim, 1996). A number of
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dopamine-antagonizing medications also have well-documented utility in the control of centrally induced gastrointestinal disturbance, and are given to a variety of patient populations for this purpose (Fernando & Eisendrath, 1991). Metoclopramide is a dopaminergic antagonist that is rarely used for psychiatric purposes, but is an anti-emetic thought to control nausea and vomiting through dopamine antagonism in the chemoreceptor trigger zone in the medulla oblongata (Gralla et al., 1981). As with many medications with antidopaminergic properties, metoclopramide has been associated with the same adverse motor side effects demonstrated by antipsychotic medications, including dystonia (Grimes, Hassan, & Preston, 1982), akathisia (Granzini, Casey, Hoffman, & McCall, 1993), and TD (Granzini et al., 1993; Miller & Jankovic, 1989; Sewell & Jeste, 1992; Sewell, Kodsi, Caligiuri & Jeste, 1994; Wilholm, Mortimer, Boethius, & Haggstrom, 1984). In a review of the literature on metoclopramide-induced TD, Sewell and Jeste (1992) found 67 case reports in which this medication was implicated in TD development. Although there is less awareness of the risk of such side effects with metoclopramide use, the existing literature in the general population reports that side effects are not uncommon (Jeste & Caligiuri, 1993). To date, no studies investigating the incidence of TD in persons with mental retardation taking metoclopramide have been conducted. Given the high incidence of gastrointestinal disturbance in persons with mental retardation and the popularity of this medication to treat such problems, mentally retarded individuals taking this medication could be at risk for developing metoclopramide-induced movement disorders. We examined the incidence of TD in 25 persons with mental retardation who were taking metoclopramide. We compared scores on a standardized measure of TD of these individuals with 25 individuals with mental retardation who were taking typical antipsychotic medications, and with a third group of mentally retarded individuals who were not taking metoclopramide or psychotropic medication. Participants were matched on age, sex, and severity of mental retardation. Analyses were conducted to identify differences in incidence of TD between the two groups, as well as the course of TD in both groups over a 1-year time period. 2. Method 2.1. Participants We obtained information on 75 adults with mental retardation, all of whom resided at Pinecrest Developmental Center in Pineville, LA. Individuals were assigned to one of three groups (N 25 in each case) depending on type of medication administered: (a) metoclopramide; (b) typical antipsychotics (thioridazine, chlorpromazine or haloperidol); or (c) no metoclopramide or psychotropic medication. Where possible, we matched the groups on an individual basis for three factors: (a) age, (b) sex, and (c) level of mental retardation. In addition, we obtained information from medical records regarding (a) Axis I diagnoses and (b) other psychotropic medications for each participant.
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A number of participants had received a variety of Axis I diagnoses, including Autism or Pervasive Developmental Disorder (N 10), Bipolar Disorder (N 2), Impulse Control Disorder (N 4), Schizophrenia (N 3), Intermittent Explosive Disorder (N 1), Pica (N 1), and Stereotypic Movement Disorder with Self-Injurious Behavior (SIB) (N 13) and without SIB (7). Thirty-®ve participants did not have an Axis I diagnosis, the majority of which were in the metoclopramide (N 16) and no psychotropic medication groups (N 19). Participants were matched for the variables of age (mean age of 39 in metoclopramide, 41 in typical antipsychotic group, and 40 in no psychotropic group), gender (9 males, 16 females in the metoclopramide group, 10 males and 15 females in both the typical antipsychotic and no psychotropic groups), and level of mental retardation (3 severe and 22 profound in the metoclopromide group; 3 moderate, 5 severe, and 17 profound in typical antipsychotic group; and 1 mild, 5 moderate, 5 severe, and 14 profound in the no psychotropic group). Regarding medication dose, participants in the metoclopramide group averaged 33 mg per day, and participants in the typical antipsychotic group averaged 211 mg per day (CPZ equiv. dose); doses of medication for both groups remained stable throughout the study with the exception of three participants in the metoclopramide group (each had one 10 mg per day reduction) and ®ve participants in the antipsychotic group (each had a CPZ equivalent of 100 mg per day reduction). Five participants in the metoclopramide group were taking concurrent psychotropic medications, all of whom were taking only one psychotropic. Types of psychotropic medications included mood stabilizers (N 3), antidepressants (N 1) and beta blockers (N 1). Other relevant concurrent medications taken in this group included anti-convulsants (N 19) and antihistamines (N 1). Ten individuals in the typical antipsychotic medication group were taking concurrent psychotropic medications (9 taking a total of two psychotropics, 1 taking three psychotropics), including mood stabilizers (N 6), anxiolytics (N 2), and anticholinergics (N 1). Other relevant concurrent medications taken in the antipsychotic group included anti-convulsants (N 2) and antihistamines (N 1). Speci®c histories of metoclopramide and typical antipsychotic medication use was not obtained due to availability of medication history records for 4 previous years only. However, available records con®rmed that participants in the metoclopramide group did not have a history of exposure to any other dopamine blocking agents. Additionally, records revealed that participants in the metoclopramide and typical antipsychotic groups had received their respective medications for at least 4 years, and participants in the no psychotropic medication control group had never received an antipsychotic or metoclopramide. 2.2. Instruments Participants were evaluated with the DISCUS, a standardized measure of TD (Sprague & Kalachnik, 1991). The DISCUS is a 15-item rating scale designed to identify dyskinetic movements in seven bodily areas: the face, eyes, oral (jaw,
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lips), lingual (tongue), head, upper limbs, and lower limbs. Each item is a symptom (e.g., blinking, tongue tremor, pill rolling) that is rated on a 5-point severity scale, with a score of 0 indicating the symptom is not present and a score of 4 indicating the symptom is severe. Rankings of 1±4 re¯ect severities of minimal, mild, moderate, and severe, respectively. A total score of 5 or greater indicates probable TD; two consecutive scores of 5 indicate persistent TD. Normative data for persons with mental retardation is available for this scale, and the DISCUS has also proven reliable and valid with this population (Sprague & Kalachnik, 1991). 2.3. Procedure Participants in the metoclopramide and typical antipsychotic groups were evaluated with the DISCUS at 3-month intervals a total of four times as part of a mandated routine quarterly examination for medication side-effects. Thus, this study was a retrospective review as opposed to a prospective study. Because they were not routinely assessed for medication side effects, the no psychotropic medication control group was evaluated with the DISCUS on only one occasion that corresponded to the fourth administration in the other two groups. The DISCUS was administered by one of four trained raters, all of whom were graduate students in a Ph.D. clinical psychology training program and had been employed at the developmental center for at least 1 year. Raters received initial training in DISCUS administration and scoring from viewing the DISCUS training videotape and from individual instruction from a senior Ph.D. student who received DISCUS training from a board-certi®ed psychiatrist. Maintenance training was conducted approximately twice yearly through subsequent showings of the videotape. All raters were pro®cient in distinguishing between TD related abnormal movement and other types of potentially confounding movement, such as stereotypies. All DISCUS were conducted in a quiet setting at the participant's home or training facility; administration and scoring time averaged 7 min per client. 3. Results We conducted several analyses to determine differences among the groups on pertinent variables. First, to determine differences among the metoclopramide and typical antipsychotic groups for total DISCUS scores, we conducted a oneway repeated measures analysis of variance (ANOVA) using DISCUS total score as the dependent variable. A signi®cant main effect for time was found [F 2:76; 132 2:99, p :04] (df and p-value corrected using Huynh±Feldt correction for violation of sphericity assumption). A main effect for group was not found [F 1; 48 :02, p :88], nor was a time by group interaction [F 2:76; 132 :52, p :65]. Trend analyses revealed the presence of negative linear trends for both metoclopramide and typical antipsychotic groups for total DISCUS score [F 1; 48 4:33, p :04]. Mean DISCUS scores for the
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Fig. 1. Mean DISCUS scores by participant group across four administrations. No statistical difference was found among the metoclopramide and typical antipsychotic groups across administrations; however, a signi®cant negative linear trend for both groups' scores was identi®ed [F 1; 48 4:33, p :04]. A signi®cant difference among all three groups was found on the fourth DISCUS administration [F 2; 27 3:51, p :04]. Pairwise comparisons indicated that participants taking typical antipsychotics displayed signi®cantly more overall symptoms of TD than did participants taking no psychotropics; the metoclopramide group did not differ from either of the other two.
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metoclopramide and typical antipsychotic groups across administrations are displayed in Fig. 1. Next, a separate one-way ANOVA using the fourth DISCUS administration as the dependent variable was conducted to detect differences between all three groups. A signi®cant difference was detected for total DISCUS score [F 2; 72 3:51, p :04]. Pairwise comparisons (Tukey HSD test) indicated that participants taking typical antipsychotics displayed signi®cantly more overall symptoms of TD than did participants taking no psychotropics; the metoclopramide group did not differ from either of the other two. To further examine differences in probable presence of TD, differences among groups regarding scores that exceeded the recommended cutoff score of 5 were examined. First, the difference between the two medication groups for number of individuals exceeding the cutoff score of 5 for two consecutive administrations (criteria for persistent TD) was examined. A single dichotomous score was Table 2 Mean score of individual items across administrations and percentage of successful DISCUS item administrations for metoclopramide and typical antipsychotic groups Category and Item
Metoclopramide Group
Typical Antipsychotic Group
Mean
% Assessed
Mean
% Assessed
Face Tics (item 1) Grimaces (item 2)
.07 .20
100 100
.13 .09
100 100
Eyes Blinking (item 3)
.11
100
.06
100
.47 .38
100 100
.57 .45
100 100
.64
92
.22
91
.20 .07 .23
82 76 76
.14 .38 .35
83 78 77
.07 .01
100 100
.07 .01
100 100
Oral Chewing/lip smacking (item 4) Puckering/sucking/thrusting lower lip (item 5) Lingual Tongue thrusting/tongue in cheek (item 6) Tonic tongue (item 7) Tongue tremor (item 8) Athetoid/myokymic lateral tongue (item 9) Head/neck/trunk Retrocollis/torticollis (item 10) Shoulder/hip torsion (item 11) Upper limb Athetoid/myokymic ®nger±wrist±arm (item 12) Pill rolling (item 13)
.04
99
.12
100
.22
99
.23
100
Lower limb Ankle ¯exion/foot tapping (item 14)
.13
98
.06
85
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derived based on whether the recommended TD cutoff score of 5 was exceeded at least twice during the four administrations for the metoclopramide and antipsychotic groups. Chi-square analysis did not reveal a statistically signi®cant difference in TD status among the two groups, w2 1 1:50, p :221. Two individuals in the metoclopramide group met criteria for persistent TD, while ®ve met this criteria in the typical antipsychotic group. Next, a single dichotomous score was derived based on whether the recommended TD cutoff score of 5 was exceeded only once during the four administrations for the metoclopramide and antipsychotic groups, and during the one administration for the no drug controls. Chi-square analyses revealed a statistically signi®cant difference in TD status among the three groups, w2 2 10:71, p :005. Ten individuals in each medication group met criteria for probable TD at least once, while only one individual in the no psychotropic control group exceeded this cutoff. The majority of participants were compliant with the standard DISCUS instructions, which include opening one's mouth, sticking out one's tongue, and removing shoes and socks. However, some participants did not comply with all requests. The percentage of successful administrations for each item as well as item means across administrations are presented in Table 2. 4. Discussion We examined the TD pro®les of persons with developmental disabilities who were receiving either metoclopramide, typical antipsychotics, or no psychotropic medications over a 1-year period. Our analyses showed no signi®cant difference in total DISCUS scores between persons taking either metoclopramide of typical antipsychotic medication, with both groups averaging scores below TD threshold on each assessment occasion. Additionally, an analysis of individuals in each group meeting criteria for persistent TD indicated that while several individuals in each group met criteria for persistent TD, the differences between the groups failed to reach statistical signi®cance. However, comparisons between all three groups for meeting probable TD criteria on at least one occasion indicated that a signi®cantly higher number of participants in both medication groups met criteria for probable TD than participants in a no psychotropic control group. Several points about metoclopramide-induced TD in persons with mental retardation emerged. First, our results are consistent with reports of metoclopramide-induced TD in the general population; that is, like traditional antipsychotic agents, metoclopramide can lead to symptoms of TD in persons with mental retardation. Of 50 participants taking either metoclopramide or typical antipsychotics, 10 (40%) in each group met criteria for probable TD at some point during a year's time, a number signi®cantly higher than matched controls. Second, our ®ndings illustrate that metoclopramide-induced TD, like antipsychotic-induced TD, may vary signi®cantly in severity over time, underscoring the need for repeated assessment in clinical settings (Gardos, Cole, Schniebolk, & Salomon, 1987).
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The overall severity of TD symptoms seen in both the metoclopramide and antipsychotic groups was relatively low, and a general downward trend of scores was observed in both groups across the four assessment periods. The reasons for this are not clear. However, individuals in both groups had been taking their respective medications for a number of years, and it is likely that they received medical attention for TD (e.g., increases or decreases in medication dose). Additionally, the stability of medication dose in both medication groups may have obscured the presence TD, as symptoms may present only when medication is withdrawn (Wilson et al., 1998). Medication dose may have also contributed to low scores; both groups were receiving low to modest average doses of respective medication, with the typical antipsychotic group receiving an average of 211 CPZ equiv. mg per day (standard range is 200±800 mg per day; Baldessarini, 1996). While the role of dose on the development of TD is somewhat unclear (Jeste & Caligiuri, 1993), it is possible that this factor combined with close monitoring of TD symptoms by developmental center staff may account for low total DISCUS scores. The downward trend in scores in both groups is statistically signi®cant, but an inspection of group mean scores reveals that the difference in scores from ®rst administration to last is less than one point. It is possible that some participant noncompliance led to underestimation of some TD symptomatology. As shown in Table 2, some items in the lingual and upper and lower limb areas were not assessed; with the exception of ``toe movement,'' both groups were relatively equal in the number of administrations failing to yield a valid score in these areas. Thus, the possibility exists that the DISCUS scores presented here re¯ect a more conservative estimate, especially given the tendency of TD symptoms to present in the lingual area in persons with mental retardation relative to the general psychiatric population (Cohen et al., 1991). While full compliance on all items would produce the most accurate estimates of TD, this is often dif®cult to achievewith individuals who may not understand experimenter requests. Given that only one item fell below the 75% level (toe movement, 55%) and the majority of DISCUS items were administered with 100% compliance, our testing efforts with this population were viewed as successful. All three groups contained participants who had been diagnosed with a Stereotypic Movement Disorder, the majority of whom were in the typical antipsychotic group. This was of some initial concern given possible confusion of TD symptoms and stereotypic movements. However, the majority of TD symptoms observed were those which would not likely be confused with stereotypic movements (e.g., oral±facial). Hip and shoulder torsion and retrocolis/torticolis, two groups of movements that would have been the most likely to be confused with TD symptoms, were observed to occur very infrequently in our sample. Thus, confusion of these two classes of movements was not likely and not considered to be a threat to the validity of our ®ndings. Future studies of metoclopramide-induced TD in persons with mental retardation are warranted given our results. Examination of a larger number of individuals may elucidate information that have gone undetected in our study due to a low number of subjects. An examination of incidence of TD following
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metoclopramide discontinuation or downward titration in dose would also help clarify the potential for metoclopramide-induced TD to develop in persons with mental retardation. References Baldessarini, R. J. (1996). Drugs and the treatment of psychiatric disorders: Psychosis and anxiety. In J. G. Hardman & L. E. Limbird (Eds.), Goodman and Gilman's: The pharmacological basis of therapeutics (9th ed., pp. 431±459). New York: McGraw-Hill. Cohen, S., Khan, A., Zheng, Y., & Chiles, J. (1991). Tardive dyskinesia in the mentally retarded: Comparison of prevalence, risk factors and topography with a schizophrenic population. Acta Psychiatrica Scandinavica, 83, 234±237. Fernando, S. J., & Eisendrath, S. J. (1991). Adverse neuropsychiatric effects of dopamine antagonist medications: Misdiagnosis in the medical setting. Psychosomatics, 32, 426±432. Gardos, G., Cole, J. O., Schniebolk, S., & Salomon, M. (1987). Comparison of severe and mild tardive dyskinesia: Implications for etiology. Journal of Clinical Psychiatry, 48, 359±362. Gralla, R. J., Itri, L. M., Pisko, S. E., Squilante, A. E., Kelsen, D. P., Braun, D. W., Bordin, L. A., Braun, T. J., & Young, C. W. (1981). Antiemetic efficacy of high-dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. New England Journal of Medicine, 305, 905±909. Granzini, L., Casey, D. E., Hoffman, W. F., & McCall, A. L. (1993). The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Archives of Internal Medicine, 28, 1469±1475. Grimes, J. D., Hassan, M. N., & Preston, D. N. (1982). Adverse neurologic effects of metoclopromide. Canadian Medical Association Journal, 126, 23±25. Jeste, D. V., & Caligiuri, M. P. (1993). Tardive dyskinesia. Schizophrenia Bulletin, 19, 303±314. Matson, J. L., Bamburg, J. W., Mayville, E. A., & Logan, J. R. (2000). Tardive dyskinesia and developmental disabilities: An examination of demographics and topography in persons with dual diagnosis. British Journal of Developmental Disabilities, 46, 117±128. McKim, W. A. (1996). Drugs and behavior: An introduction to behavioral pharmacology (3rd ed.). Upper Saddle River, NJ. Miller, L. G., & Jankovic, J. (1989). Metoclopramide-induced movement disorders: Clinical findings with a review of the literature. Archives of Internal Medicine, 149, 2486±2492. Richardson, M., Haugland, G., Pass, R., & Craig, T. J. (1986). The prevalence of tardive dyskinesia in a mentally retarded population. Psychopharmacology Bulletin, 22, 243±249. Sewell, D. D., & Jeste, D. V. (1992). Metoclopramide-associated tardive dyskinesia: An analysis of 67 cases. Archives of Family Medicine, 1, 271±278. Sewell, D. D., Kodsi, A. B., Caligiuri, M. P., & Jeste, D. V. (1994). Metoclopramide and tardive dyskinesia. Biological Psychiatry, 36, 630±632. Sprague, R. L., & Kalachnik, J. E. (1991). Reliability and a total score cutoff for the Dyskinesia Identification System: Condensed User Scale (DISCUS) with mentally ill and mentally retarded populations. Psychopharmacology Bulletin, 27, 51±58. Youseff, H. A., & Waddington, J. L. (1988). Involuntary orofacial movements in hospitalised patients with mental handicap or epilepsy: Relationship of developmental intellectual deficit and presence or absence of long-term exposure to neuroleptics. Journal of Neurology, Neurosurgery, and Psychiatry, 51, 863±865. Wilholm, B. E., Mortimer, O., Boethius, G., & Haggstrom, J. E. (1984). Tardive dyskinesia associated with metoclopramide. British Medical Journal, 288, 545±547. Wilson, J. G., Lott, R. S., & Tsai, L. (1998). Side effects: Recognition and management. In S. Reiss & M. G. Aman (Eds.), Psychotropic medications and developmental disabilities: The international consensus handbook (pp. 95±114). Columbus, OH: The Ohio State University Nisonger Center.