Charles E. Dean

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

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.

Antipsychotic-associated neuronal changes in the brain: Toxic, therapeutic, or irrelevant to the long-term outcome of schizophrenia?

The increasingly wide-spread use of antipsychotics in both adults and children calls for a detailed examination of antipsychotic-associated neuronal changes in the brain, and whether these changes are toxic, therapeutic, or perhaps irrelevant to the outcome of major psychiatric disorders, especially schizophrenia. In this review we will examine the extensive evidence demonstrating both acute and longer-term antipsychotic-associated neurotoxicity and neuroplasticity, as well as the more specific cellular changes that appear to underlie these phenomena. These include changes in proteins affecting cell survival, impairment of the mitochondrial respiratory chain, increases in DNA fragmentation, injury to dendritic microtubules, increases in dopamine-generated reactive oxygen species, changes in cell morphology, and rapid induction of apoptosis. We shall also examine the correlation between these changes and alterations in gross brain structure. There appears to be a disjunction between the widespread cellular and gross structural brain changes in schizophrenia, and the duration of illness, expression of symptoms, and response to treatment. We shall explore possible explanations for this apparent paradox.

Prasterone (DHEA) and Mania

OBJECTIVE: To inform clinicians and investigators of the potential for severe mania in conjunction with the use of prasterone (DHEA; dehydroepiandrosterone). CASE SUMMARY: A 31-year-old Hispanic man was admitted on a 72-hour observation period from a neighboring hospital after threatening to kill himself, family members, and a friend. A loaded rifle was found under his bed. The family confirmed that he had begun using DHEA several weeks prior to his mood and behavioral changes. He denied any past violence, but had once been given an unsubstantiated diagnosis of bipolar disorder. He used alcohol episodically, and had difficulties controlling his anger while intoxicated. Although he improved with valproate, his threats of homicide led to involuntary commitment. DISCUSSION: Several studies and case reports strongly suggest that anabolic steroids can induce significant psychiatric difficulties, including mania, impaired cognition, and overt psychosis. Although the Food and Drug Administration noted in 1985 that the efficacy and safety of DHEA were never confirmed, the agent continues to be sold over the counter. Several groups have used DHEA in the treatment of AIDS, memory loss, and depression, but reported no serious adverse events; however, recent studies indicate that severe psychiatric symptoms can develop in a subset of users. Although uncertain, potential risk factors include high doses of DHEA; history of mood disorder; concurrent use of alcohol, street drugs, or antidepressants; and cytochrome P450 polymorphisms. CONCLUSIONS: The use of DHEA in those under age 35 years may be especially risky, as endogenous DHEA concentrations peak at age 20–30 years. Those using or investigating DHEA should be cognizant of the potential for severe psychiatric complications.

Handwriting movement analyses for monitoring drug-induced motor side effects in schizophrenia patients treated with risperidone

Epidemiologic studies indicate that nearly 60% of schizophrenia (SZ) patients treated with conventional antipsychotic drugs develop extrapyramidal side effects (EPS) such as parkinsonism and tardive dyskinesia. Although the prevalence of EPS has decreased due to the newer antipsychotics, EPS continue to limit the effectiveness of these medicines. Ongoing monitoring of EPS is likely to improve treatment outcome or compliance and reduce the frequency of re-hospitalization. A quantitative analysis of handwriting kinematics was used to evaluate effects of antipsychotic medication type and dose in schizophrenia patients. Twenty-seven schizophrenia patients treated with risperidone, six schizophrenia patients who received no antipsychotic medication and 47 healthy comparison participants were enrolled. Participants performed a 20-min handwriting task consisting of loops of various sizes and a sentence. Data were captured and analyzed using MovAlyzeR software. Results indicated that risperidone-treated participants exhibited significantly more dysfluent handwriting movements than either healthy or untreated SZ participants. Risperidone-treated participants exhibited lower movement velocities during production of simple loops compared to unmedicated patients. Handwriting dysfluency during sentence writing increased with dose. A 3-factor model consisting of kinematic variables derived from sentence writing accounted for 83% (r=.91) of the variability in medication dose. In contrast, we found no association between observer-based EPS severity ratings and medication dose. These findings support the importance of handwriting-based measures to monitor EPS in medicated schizophrenia patients.

Clinical rating scales and instruments: How do they compare in assessing abnormal, involuntary movements?

Objective: Recent studies have shown that quantitative instrumental measurements are more sensitive than clinical rating scales to subclinical dyskinesia and parkinsonism. We therefore hypothesized that an instrumental assessment would be more sensitive to the presence of dyskinetic and parkinsonian movements than the Abnormal Involuntary Movement Scale (AIMS), the Dyskinesia Identification Scale, Condensed User Version (DISCUS), and the Simpson-Angus Scale (SAS). We also hypothesized that the DISCUS, by virtue of its more detailed protocol, would be more sensitive than the AIMS. Method: Using blinded raters, we compared the clinical rating scales with instrumental measurements in 100 patients referred to a movement disorders clinic. We collected demographic data, risk factors for tardive dyskinesia, current medication use, Axis I and III disorders, and an estimate of cognitive functioning using the Mini-Mental Status Examination. Results: There was no significant difference between the AIM and the DISCUS in the identification of dyskinesia. However, an instrumental assessment revealed a significantly greater prevalence of dyskinesia. The Mini-Mental Status Examination was the most prominent predictor of both instrumental and clinical measurements of parkinsonian and dyskinetic movements. Conclusions: It appears that even trained raters, utilizing standard rating scales, may underestimate the prevalence of some motor abnormalities. Instrumental ratings may be helpful to both the clinician and investigator, particularly when abnormal movements are not clinically obvious. The relationship between cognitive impairment and motor abnormalities remains an important area for further research.

Predictors of neuroleptic-induced dyskinesia and parkinsonism: the influence of measurement methods and definitions.

The accurate and objective measurement of abnormal, involuntary movements remains highly desirable, whether the movements are secondary to pharmacotherapy or an expression of the primary illness. In a previous study, we found that the prevalence of tardive dyskinesia in a sample of 100 subjects ranged from 28% when using the Abnormal Involuntary Movement Scale (AIMS) or the Dyskinesia Identification Scale, Condensed User Version (DISCUS) to 62% using an instrumental measurement (IM) of peripheral dyskinesia. The goal of this study was to examine the relationship between various risk factors for tardive dyskinesia as predictor variables, and the AIMS, DISCUS, and IMs of dyskinesia, tremor, and velocity of motor movement as dependent variables. The sample consisted of 100, mostly patients with schizophrenia. Poor performance on the Mini-Mental State Examination (MMSE) and increasing age were the most consistent predictors of dyskinetic and parkinsonian movements. Various predictors were associated with specific abnormal movements. Head injury was related to slower speed of motor movements and the total DISCUS score. A history of smoking was associated with less IM dyskinesia. For those with coexisting parkinsonism and dyskinesia, significant associations were found with head injury, diabetes mellitus, and an AIMS score of 2 or greater in 2 body areas. Various classes of psychotropic agents seemed to have little influence on the MMSE or the development of dyskinesia and parkinsonism. Increasing age and a lower score on the MMSE seem to be particularly helpful in gauging the risk for parkinsonian and dyskinetic movements.

Personalized Medicine: Boon or Budget-Buster?

While the development of personalized or molecular medicine is a laudable goal, there remain multiple barriers to its implementation. For example, little is known about the functions of noncoding regions of DNA, as well as the interplay of drug response, environmental factors, and the patients genetic profile. In addition, there is a constant influx of new information on genetic factors such as epigenetic variation that could further complicate the development of medications based on the genetic profile, as well as the cost of profiling. However, assuming that clinically relevant genetic factors will be discovered and that drugs can be developed based on the molecular changes induced by those genetic factors, I suggest that the costs involved may substantially exceed the savings brought about by abandoning our current “one drug fits all” approach. While there is no doubt that our current approach is inefficient and expensive, remarkably little attention has been paid to the potential costs of molecular medicine. Given the current economic crisis, the time is ripe for a debate on this issue.

Psychopharmacology: a house divided.

BACKGROUND Psychopharmacology and psychiatry during the past 50 years have focused on the specificity model in which it is assumed that psychiatric disorders are specific entities which should respond to drugs with specific mechanisms of action. However, the validity of this model has been challenged by the approval of multiple drugs for the same disorder, as well as the approval of single agents for a variety of disorders which have little in common. As an example of this unacknowledged paradigm shift, I will examine the foundation for using antipsychotics in the treatment of depression. METHODS An extensive literature search of studies investigating various mechanisms of actions of antipsychotics and antidepressants with the goal of identifying neurochemical processes common to both. RESULTS The neurochemical differences in these classes of drugs appear to be profound, although several processes are common in both, including some degree of neuroprotection and changes in the epigenome. Whether these common features have any effect on clinical outcome remains in doubt. CONCLUSIONS While psychopharmacology and psychiatry remain largely committed to the specificity model, it appears that clinicians are prescribing on a dimensional model wherein symptoms are being treated with a variety of drugs, regardless of the diagnosis.

A Quantitative Measure of Handwriting Dysfluency for Assessing Tardive Dyskinesia

Abstract Tardive dyskinesia (TD) is a movement disorder commonly associated with chronic exposure to antidopaminergic medications, which may be in some cases disfiguring and socially disabling. The consensus from a growing body of research on the incidence and prevalence of TD in the modern era of antipsychotics indicates that this disorder has not disappeared continues to challenge the effective management of psychotic symptoms in patients with schizophrenia. A fundamental component in an effective strategy for managing TD is its reliable and accurate assessment. In the present study, we examined the clinical utility of a brief handwriting dysfluency measure for quantifying TD. Digitized samples of handwritten circles and loops were obtained from 62 psychosis patients with or without TD and from 50 healthy subjects. Two measures of dysfluent pen movements were extracted from each vertical pen stroke, including normalized jerk and the number of acceleration peaks. Tardive dyskinesia patients exhibited significantly higher dysfluency scores than non-TD patients and controls. Severity of handwriting movement dysfluency was correlated with Abnormal Involuntary Movement Scale severity ratings for some tasks. The procedure yielded high degrees of test-retest reliability. These results suggest that measures of handwriting movement dysfluency may be particularly useful for objectively evaluating the efficacy of pharmacotherapeutic strategies for treating TD.

Imipramine-Associated Hyperpigmentation

OBJECTIVE: To inform clinicians of the potential for severe and persistent facial hyperpigmentation with the long-term use of imipramine. CASE SUMMARY: A 65-year-old white male veteran with a history of paranoid schizophrenia was referred to the psychiatry service by a dentist who thought that the patient was both cyanotic and psychotic. The history and biopsy results indicated the possibility of imipramine-associated hyperpigmentation, only the second reported case in a male patient. The presentation was complex, with a history of neuroleptic exposure and multiple signs of parkinsonism. A brain single photon-emission computed tomography scan demonstrated frontal lobe hypermetabolism and bilateral caudate hypermetabolism, which normalized 14 months later. Despite discontinuation of imipramine, the patient continued to appear cyanotic, leading to worsening social isolation. He became known as “the man with the purple face.” On his rare ventures outside the home, he was embarrassed by sporadic calls to 911 by persons fearing he was ill. DISCUSSION: Although facial hyperpigmentation secondary to the use of phenothiazines has been reported frequently, it is much less common with imipramine, and is very rare in males. Failure to recognize this adverse reaction led to continuing treatment with imipramine and to an apparently irreversible condition. The brain imaging findings have no link with the hyperpigmenting process, but raise questions about neuroleptic-induced metabolic changes in the brain. CONCLUSIONS: Clinicians need to be aware of rare adverse reactions such as hyperpigmentation, and be prepared to take appropriate and early action to prevent such reactions from becoming irreversible.