Handwriting movement kinematics for quantifying extrapyramidal side effects in patients treated with atypical antipsychotics

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Abstract

Ongoing monitoring of neuroleptic-induced extrapyramidal side effects (EPS) is important to maximize treatment outcome, improve medication adherence and reduce re-hospitalization. Traditional approaches for assessing EPS such as Parkinsonism, tardive akathisia, or dyskinesia rely upon clinical ratings. However, these observer-based EPS severity ratings can be unreliable and are subject to examiner bias. In contrast, quantitative instrumental methods are less subject to bias. Most instrumental methods have only limited clinical utility because of their complexity and costs. This paper describes an easy-to-use instrumental approach based on handwriting movements for quantifying EPS. Here, we present findings from psychiatric patients treated with atypical (second generation) antipsychotics. The handwriting task consisted of a sentence written several times within a 2 cm vertical boundary at a comfortable speed using an inkless pen and digitizing tablet. Kinematic variables including movement duration, peak vertical velocity and the number of acceleration peaks, and average normalized jerk (a measure of smoothness) for each up or down stroke and their submovements were analyzed. Results from 59 psychosis patients and 46 healthy comparison subjects revealed significant slowing and dysfluency in patients compared to controls. We observed differences across medications and daily dose. These findings support the ecological validity of handwriting movement analysis as an objective behavioral biomarker for quantifying the effects of antipsychotic medication and dose on the motor system.

Introduction

Neuroleptic medications have been the mainstay for treating psychotic illness for over 50 years. While neuroleptics improve the lives of schizophrenic patients, the occurrence of neuroleptic-induced extrapyramidal side effects (EPS) with increasing dosage often imposes limits on the dosage actually required to treat the disease. Even after the emergence of second generation antipsychotics, EPS continue to cause concern (Miller et al., 2008), particularly in vulnerable populations, such as the elderly (Caligiuri et al., 2000).

Ongoing monitoring of EPS is important to maximize treatment outcome, improve medication adherence and reduce re-hospitalization. Effective management of EPS begins with early detection, and eventually, prevention. Early detection of EPS requires sensitive and reliable measurement. Traditional means of assessing EPS rely upon observer judgments of severity, but these subjective ratings suffer from low reliability, even after the required extensive training, and are insensitive to mild subclinical abnormalities (Lohr and Caligiuri, 1992, Caligiuri, 1997). Different examiners show different average judgments of the same patients, resulting in examiner bias. To overcome these limitations, investigators have developed instruments for quantifying EPS (e.g., load cells, strain gauges, accelerometers, and electromyograms). While these instruments enjoyed appeal in research settings, they have not been adopted for routine clinical or bedside use. The main reason is because these procedures require levels of technical expertise not always available in clinical settings. Currently, no techniques for the quantitative and objective measurement of EPS severity are available that can be easily used by neurologists, psychiatrists, and other practitioners in the clinical setting.

One such approach to quantifying drug-induced motor side effects involves the analysis of handwriting movements. Haase (1961) was the first to demonstrate a relationship between the clinical effectiveness of neuroleptic mediation and EPS using handwriting analysis. Haase noted that as neuroleptic dosage increased, patients showed Parkinsonism; their handwriting slowed (bradykinesia) and decreased in size, resembling the micrographia observed in Parkinson's disease. The use of handwriting movements to assess EPS has been a focus of research primarily in Europe (Haase, 1978, Gerken et al., 1991, Künstler et al., 1999, Künstler et al., 2000). However, the results have been mixed. For example, Gerken et al. (1991) used movement size (expressed by the area encompassed by handwriting) in schizophrenic patients for predicting treatment response. In their small sample of patients, they observed reductions in handwriting size in three of the nine treatment responders and in nine of the 12 treatment non-responders, suggesting that the handwriting movement size was unable to predict treatment response. Künstler et al. (2000) used single photon emission tomography to examine the relationship between the handwriting area and the dopamine D2 receptor occupancy in schizophrenic patients before and after treatment with haloperidol, clozapine, or risperidone. They reported a highly significant linear relationship between the D2 receptor occupancy and the reduction in handwriting area. In a second study of 10 schizophrenic patients who received medication for the first time, Regenthal et al. (2005) reported positive correlations between the D2 receptor occupancy, the plasma level of risperidone and its active metabolite 9-hydroxyrisperidone and the reduction in handwriting area. While none of the patients exhibited clinically observed EPS, the authors concluded that the analysis of handwriting movements might be well suited for evaluating the neurological side effects of neuroleptic medications because of their sensitivity to D2 receptor occupancy.

The purposes of the present study were to test whether handwriting kinematic measures show greater impairments for some atypical antipsychotic medication than for others and whether the severity of impairment is related to the daily dose. Additionally, we aimed to compare the medication and dose effects on handwriting kinematics with those for traditional observer-based EPS severity ratings.

Section snippets

Subjects

This study involved a multi-site parallel group design. Subjects were recruited and tested at the three sites including: San Diego, CA; Minneapolis, MN; and Indianapolis, IN. The study was carried out in accordance with the 1964 Declaration of Helsinki and all subjects signed institution-approved informed consent prior to participating. Subjects from each site received the same clinical evaluation and a computer-controlled handwriting motor test in the same order, using the same procedures. The

Instrument reliability

Table 2 shows the results of the instrument reliability testing where each of the replications is considered an independent test. With the possible exception of the calculation of the APKsub, all of the handwriting kinematic variables exhibited high repeatability (with Cronbach's α coefficients raging from 0.76 to 0.95). The relatively low coefficient for the APKsub (0.57) indicates that this variable may be measuring a multidimensional rather than a unidimensional latent construct.

Patient versus control group effects

Table 3

Discussion

The present study revealed several novel findings with respect to the handwriting movement for patients treated with atypical antipsychotics. First, in contrast to the healthy individuals, the medicated patients exhibited abnormalities on several kinematic features of handwriting including movement duration, peak vertical velocity, smoothness, and number of acceleration peaks. Abnormalities were observed at the level of the individual stroke as well as submovements within a stroke. Second, we

Acknowledgments

This research was supported by NIH Grant R44 MH073192. The authors acknowledge Todd May (San Diego), James Tacklind and Jean Russell (Minneapolis), and Nabeel Yehyawi, Craig Dike, Jeremy Davis, and Dave Bertram (Indianapolis) for their contributions in recruiting and assessing subjects and data management.

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