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A National Research Council report on strengthening forensic science raised concern over the lack of scientific studies supporting the validity of examining and interpreting forensic evidence. However, establishing the foundational validity of subjective methods can be challenging. The present study aimed to establish the scientific validity of expert writership opinions and the two-stage approach to evidence interpretation using measures derived from research on handwriting motor control. Regression-based procedures were used to address two experimental questions: 1) what are the relative contributions of kinematic and pressure features in predicting examiner support for alternate writership propositions when examining pairs of questioned handwriting samples; and 2) to what extent does information about the rarity of the kinematic feature dissimilarity scores improve the accuracy of a predictive model based on dissimilarity alone. Regarding the first question, we identified a multifactor model consisting of feature dissimilarity scores and their population distributions having correlation coefficients (R2) of 0.84 and 0.88 for the same-writer and different-writers propositions, respectively. Temporal features contributed up to 21% to the predictive value of the model, whereas spatial features contributed only 9% and pen pressure contributed up to 17%. When we compared models reflecting a single-stage process (based on feature dissimilarities) of forming opinions with models reflecting a two-stage process (based on feature dissimilarities and rarity) we found that the two-stage models had an average of 15.25% greater predictive value than single-stage models. These findings support the scientific validity of FDE writership determinations and underscore the importance of the two-stage approach for evidence interpretation.

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.

The aims of this study were to determine if dynamic parameters (duration, size, velocity, jerk, and pen pressure) differed for signing style (text-based, stylized, and mixed) and if signing style influences handwriting dynamics equally across three signature conditions (genuine, disguised, and auto-simulation). Ninety writers provided 10 genuine signatures, five disguised signatures, and five auto-simulated signatures. All 1800 signatures were collected using a digitizing tablet resulting in a database of each signature's dynamic characteristics. With genuine signatures, there were significant differences between styles for size, velocity, and pen pressure, and there were significant differences between genuine signatures and at least one of the un-natural signature conditions for all parameters. For velocity and size, these changes with condition were dependent on style. Changes with condition for the other parameters were similar for the three styles. This study shows that there are differences among natural signature styles and disguise behaviors that may be relevant in forensic signature examinations.

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.

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 46 healthy comparison participants were enrolled. Participants performed a 20-minute 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.

Persistent neuroleptic-induced movement disorders limit effective pharmacological management of psychotic disorders. Although antipsychotic switching is a common strategy for managing extrapyramidal side effects (EPSs), there is insufficient empirical support to guide the clinician. We designed the present study to examine whether patients with preexisting EPS switched to quetiapine would show greater reduction in EPS compared with control patients.Twenty-two patients with schizophrenia meeting clinical criteria for tardive dyskinesia or coexisting parkinsonism were randomized either to switch from their current antipsychotic to quetiapine (n = 13) or to remain on their current treatment (n = 9). A battery of standard clinical assessments for EPS along with electromechanical instrumental measures was administered before randomization and again 1 and 3 months postrandomization.We observed significant reduction in parkinsonism (P0.001) and akathisia (P = 0.02) based on clinical assessments and dyskinesia (P0.05) based on instrumental assessment for the quetiapine group. Subjects remaining on current treatment exhibited an increase in rigidity (P0.05) based on instrumental measures.These findings support the switching to quetiapine in the management of preexisting neuroleptic-induced extrapyramidal side effects.

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.

The primary purpose of this study was to examine motor physiology disturbances in a group of patients with bipolar disorder by using sensitive instrumental procedures. The secondary aim of the study was to examine the effects of the affective state on motor functions. The authors studied 67 individuals meeting DSM-IV criteria for bipolar disorder and 47 healthy comparison subjects. Electromechanical measures of force steadiness and scaling of movement velocity to distance were performed. The authors found that performance on the force steadiness and velocity scaling measures was significantly poorer in the subjects with bipolar disorder, with 58% and 63% of the patients scoring outside the normal range on the force steadiness and velocity scaling measures, respectively. Eighty-four percent of subjects showed impairment on either measure, and 37% showed impairment on both measures. The force steadiness and velocity scaling abnormalities appeared to occur independently of one another and also were not associated with affective state or current medication status. This study demonstrates that motor abnormalities suggestive of basal ganglia dysfunction occur in many patients with bipolar disorder.

Our understanding of hemispheric asymmetries in schizophrenia can be attributed to extensive neuropsychological and neuroimaging research on this topic; however, it has yet to be determined whether lateralized cognitive dysfunction represents a single core trait in schizophrenia or whether the lateralized impairments are domain specific. To test whether lateralized deficits are core features in schizophrenia we examined performance across a wide range of lateralized cognitive domains including attention, fluency, recognition memory, perception, and arousal. We also examined the relationship between lateralized impairments and psychotic and affective symptoms to determine whether abnormal hemispheric asymmetries were possibly state-related. The sample consisted of 43 subjects with schizophrenia and 66 normal healthy comparison subjects without psychiatric illness. Schizophrenia subjects exhibited abnormal right hemisphere performance on a test of recognition memory and abnormal left hemisphere performance on a measure of arousal. These findings suggest that lateralized cognitive disturbances in schizophrenia do not represent a single core lateralized deficit. Regarding the symptom analyses, severity of positive symptoms was related to right hemisphere cognitive impairment (including fluency and recognition memory), whereas severity of negative symptoms was related to left hemisphere cognitive impairment (including fluency). Overall, our findings suggest that lateralized dysfunction can occur in both hemispheres in schizophrenia, and that the positive psychotic symptoms may relate more to right hemisphere impairment, whereas negative psychotic symptoms may related more to left hemisphere impairment.

Individuals with bipolar disorder (BPD) exhibit motor, perceptual, and cognitive disturbances involving predominantly right hemisphere dysfunction. This asymmetry has been used to advance the hypothesis that the pathogenesis of bipolar disorder may be related to disturbances of the right cerebral hemisphere. We employed functional magnetic resonance imaging to examine hemispheric asymmetries in manic and depressed BPD. A secondary goal of the study was to examine effects of psychotropic medications on blood volume changes in the motor cortices.We studied 18 right-handed BPD and 13 right-handed normal healthy comparison subjects. Blood oxygen level dependent (BOLD) responses in the primary motor area (M1) and supplementary motor area (SMA) of both hemispheres were elicited during reaction time (RT) tasks.Healthy subjects activated the SMA in a reciprocal fashion with significantly greater activity in the left SMA for right hand trials and the right SMA for left hand trials. Depressed BPD subjects failed to show this normal reciprocity indicating a failure to suppress unwanted activity in the ipsilateral right SMA, whereas manic BPD subjects failed to suppress unwanted ipsilateral SMA activity in both hemispheres. Manic and depressed BPD subjects exhibited greater activity in the left primary motor area suggesting increased cortical excitability. BPD subjects treated with antipsychotics or mood-stabilizing medications exhibited longer RTs, lower BOLD responses in M1 and SMA, and a loss of normal hemispheric asymmetry in the SMA than untreated subjects.The presence of a right hemisphere disturbance in BPD is consistent with the hypothesis that the right hemisphere may be dominant in mood regulation. The presence of both left and right hemisphere disturbances in mania may explain the coexisting psychotic and affective symptoms observed in this condition.

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.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.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.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.

Predicting response to antidepressant medication has been a challenge to clinicians and researchers for decades. Attention has been paid to the role of motor retardation as a putative indicator of treatment response, yet previous findings have been mixed. One reason for this inconsistency may be related to the subjective nature of motor retardation and how it is assessed. In the present study, we adopted a measure of motor programming previously shown to characterize parkinsonian bradykinesia to test whether neuromotor function could predict response to antidepressant treatment. Twenty-eight patients (14 males and 14 females with a mean age of 42.0 years) meeting DSM-IV criteria for a depressive disorder were randomized to receive 8 weeks of treatment with one of three antidepressant medications (sertraline, phenelzine, or bupropion). Treatment outcomes were assessed using the 17-item version of the Hamilton Rating Scale for Depression (HRSD). Patients were considered asymptomatic if their post-treatment HRSD total score was equal to or less than 7. Treatment responders (n=15) had significantly less baseline impairment (P=0.01) on the neuromotor measure than non-responders (n=13). There was a significant relationship between amount of improvement on the HRSD and severity of baseline neuromotor function (r=-0.51; P=0.006). No significant group effects were found for baseline psychomotor slowing or clinical ratings of motor retardation. These results demonstrate that a quantitative measure of motor programming may be a useful predictor of antidepressant non-response.

Background: Cross-sectional studies in Alzheimer’s disease (AD) show a strong relationship between extrapyramidal motor signs and presence of psychosis, yet it remains unclear whether neuromotor abnormalities precede and therefore can predict development of psychosis in AD. Objective: To identify cognitive and motor risk factors for the development of psychosis in patients with AD. Methods: Baseline clinical motor ratings and instrumental measures of neuromuscular function were obtained from 54 nonpsychotic patients with AD who were evaluated annually for 2 years for the development of psychosis. Survival analyses were performed to identify incidence and risks associated with psychosis. Results: The incidence of new onset psychosis in our sample was 32.5% in 2 years. Patients with abnormal agonist muscle burst amplitudes during rapid alternating movements of the hand were more likely to develop psychosis than those without (OR = 4.31; p = 0.007). Women with AD also had a higher risk of developing psychosis within 2 years than men (OR = 1.33; p = 0.01). Conclusions: Using simple noninvasive instrumental procedures for assessing neuromotor function, it may be possible to identify an individual’s level of risk for developing psychosis during the course of AD.

Predictors for the development of tardive dyskinesia (TD) have been studied extensively over the years, yet there are few studies of predictors of the course of TD after it has developed. Moreover, few studies have examined predictors of the course of other extrapyramidal side effects (EPS) in patients maintained on neuroleptics. The purpose of this study was to determine which modifiable variables are important in the prediction of EPS in patients with persistent TD over a period of as long as 2 years. One hundred fifty-eight patients enrolled in the Veterans Affairs Cooperative Study 394 were included in this study. A linear mixed-effects (LME) analysis to estimate the Abnormal Involuntary Movement Scale score (for TD severity), Simpson-Angus Scale (for parkinsonism severity), and Barnes Akathisia Scale at any given time after intake assessment was performed. The severity of each of the TD and EPS outcomes at any given visit was predicted by their respective baseline severity scores. Additional predictors of a favorable course of TD included lower doses of antipsychotic medications and use of anticholinergic medications. Other predictors of a favorable course of EPS included younger age and the use of atypical antipsychotic medication (for rigidity) and the use of anticholinergic medication (for tremor). These findings indicate that clinician-modifiable factors related to medication usage can influence the outcome of TD and EPS in patients with persistent TD.

An accumulating body of literature supports the notion that psychotic-like experiences (PLEs) may occur as a continuous phenotype. However, researchers are still working to determine if these events accompany an underlying continuum of neurobiological vulnerability as well. Within this context, it is notable that spontaneous dyskinetic movements are linked to specific pathogenic factors underlying schizophrenia, but to date there has been little research directed towards determining whether these events are associated with PLEs. In this study, 119 individuals were assessed for PLEs and administered with a sensitive instrumental test of upper extremity dyskinesia. Present findings suggest a relationship between subtle dyskinesia and PLEs in the general population, and provide a new perspective of the psychosis continuum by indicating that basal ganglia pathology may also underlie PLEs at the non-clinical end of this spectrum.

Objective To evaluate whether the relationship between extrapyramidal signs (EPS) and cognitive disturbances in Alzheimer's disease (AD) is influenced by illness duration. Methods A multivariate regression analysis was used to study the relationships between EPS, illness duration and five cognitive ability areas based on the Mattis Dementia Rating Scale (DRS) in 89 clinically diagnosed AD patients with extrapyramidal motor involvement. Results Severity of EPS was statistically associated with performance on four cognitive ability areas from the DRS including: attention, initiation and perseveration, construction and memory. Age was a significant factor related to severity of EPS. However illness duration did not contribute to the strength of the association between EPS and cognitive disturbances in patients with AD. Conclusions The findings of the present study support the notion that while neuropsychological and motor functions often coexist in patients with AD, their relationship seems to be unrelated to degenerative processes that accumulate throughout the illness. Copyright © 2001 John Wiley & Sons, Ltd.

Neurobehavioral disturbances often coexist with extrapyramidal signs (EPS) in patients with Alzheimer's disease (AD). In the present study, we examined the relationships between delusions and hallucinations and EPS by using standard observer ratings and sensitive electromyographic (EMG) measures in 52 patients with probable AD. On the basis of observer ratings, 36.5% of the patients exhibited psychotic features and 63.5% exhibited parkinsonism. Severity of clinically rated parkinsonism and the EMG measure of bradykinesia were significantly correlated with severity of neurobehavioral disturbances in this sample. The association between parkinsonism and delusions and hallucinations suggests a subcortical mechanism in the etiopathology of psychosis in AD.

Extrapyramidal side-effects (EPSE) of antipsychotic medication are related to the occupancy of dopamine D2 receptors and there appears to be a threshold of D2 occupancy below which clinically EPSE are unlikely to occur. It is unclear whether there are motor changes produced by 'subthreshold' levels of D2 occupancy that are not detectable by clinical examination. This study was designed to investigate whether a number of electromechanical instrumental techniques could detect 'subthreshold' motor changes and whether these changes correlate with dopamine D2 occupancy as measured by [11C]-raclopride PET scan. Twenty medication naïve patients were studied before and during treatment with low dose haloperidol. Instrumental techniques detected an asymmetrical worsening in motor function with drug treatment despite the failure of the group to experience significant EPSE. These changes did not correlate with D2 occupancy and measurements of rigidity, tremor, and bradykinesia did not closely inter-correlate.

In several retrospective post-mortem studies, patients meeting clinical criteria for Alzheimer's disease (AD) who gained the greatest cognitive benefit from treatment with an acetylcholinesterase (AChE) inhibitor were found to have neocortical Lewy bodies accompanying classical AD neuropathology. This 'dementia with Lewy bodies' (DLB) subtype manifests both parkinsonian and psychopathologic features that set it apart from 'pure' AD (hereafter called AD). In the present preliminary study, 16 dementia patients were prospectively categorized as having DLB versus AD. Subjects were also categorized according to their profile on surface electromyographic (EMG) measures demonstrated in prior work to be analogues of clinically observed parkinsonian extrapyramidal signs (EPS). All patients were prescribed the AChE inhibitor donepezil (5 mg per day). At baseline and at 6 months, patients underwent cognitive testing with the Mini-Mental State Examination (MMSE) while caregivers assessed their psychopathologic status using the Behavioral Symptoms in Alzheimer's Disease (BEHAVE-AD) scale. The tester was blinded to the AD versus DLB classification of the patients. AD cases (N=12) had only a slight increase in cognitive scores, while DLB patients' (N=4) mean MMSE scores increased to a significantly greater degree. Furthermore, patients categorized by EMG as EPS positive (N=8) attained an increase in their mean MMSE score from baseline to 6 months that differed significantly from a decline in MMSE observed among their EPS negative (N=4) counterparts. For all subjects, an increase in MMSE scores across 6 months of treatment correlated with a decline in BEHAVE-AD scores.

Background: Since the prevalence of both sleep-disordered breathing (SDB) and periodic limb movements in sleep (PLMS) increase with age, we explored whether older schizophrenia patients would have a high incidence of SDB and PLMS. Correlations between sleep and clinical variables were also examined. Methods: Fifty-two patients (mean age = 59.6 years, SD = 8.9) had their sleep/wake, respiration, and leg movements recorded using a modified Medilog/Respitrace portable recording system plus oximetry. A battery of clinical, psychosocial, and motor disturbance variables were collected by research center staff. Results: Forty-eight percent of these patients had at least 10 respiratory events per hour of sleep. These patients reported more symptoms of daytime sleepiness than patients with fewer than 10 events per hour. The relatively high prevalence of SDB in this group may contribute to overall sleep disturbances, and does not appear to be a result of high body mass index. Only 14% of the patients had at least five limb movements per hour of sleep, suggesting the prevalence of PLMS is much lower than expected in this age group. The number of leg jerks was inversely related to symptoms of tardive dyskinesia. Conclusions: The disturbance of sleep in these patients may be due, in part, to SDB, but is unlikely due to PLMS.

The study of motor slowness based on observational methods has limitations. Whether motor retardation has a psychomotor or neuromotor basis is unclear because psychiatric and motor symptoms overlap. Observational methods lack the precision necessary to distinguish cognitive from motor processes. For the present study, we used an objective measure of neuromotor dysfunction to quantify the extent to which an individual programs movement velocity in anticipation of increasing target distance. Persons with Parkinson's disease (PD) or functional psychosis were studied with a group of healthy comparison subjects. Results indicated that the slope of the linear function relating velocity to distance was abnormal in the PD group and in approximately half of the psychosis group. Analyses revealed the measure to have high specificity and sensitivity. Weak correlations between velocity scaling and psychopathology support the neuromotor basis of the measure. We conclude that this measure of velocity scaling is relatively uninfluenced by cognitive factors that may underlie psychomotor retardation.

Nine VA Medical Centers are participating in a 2-year double-blind placebo controlled study of antioxidant treatment for tardive dyskinesia (TD) conducted by the Department of Veteran Affairs Cooperative Studies Program. One of the principal outcome measures of this study is the score derived from the instrumental assessment of upper extremity dyskinesia. Dyskinetic hand movements are quantified by assessing the variability associated with steady-state isometric force generated by the patient. In the present report, we describe the training procedures and results of a multi-center reliability assessment of this procedure. Data from nine study centers comprising 45 individual patients with six trials each (three from left hand and three from right hand) were reanalyzed by an independent investigator and the results were subjected to reliability assessment. For the statistic of interest (average coefficient of variation over trials 2 and 3 for each hand, then take the larger of these two values), we found very high intraclass correlation coefficients for reliability over all patients across sites (ICC = 0.995). We also calculated the reliability of the measures across trials within patient for each combination of hand (right, left, dominant), rater group (site, control), and trials set (all three, trials 2 and 3). For a given hand and trial set, the reliability of the site raters was similar to that of the control. This study demonstrates that instrumental measures for the assessment of dyskinesia are reliable and can be implemented in multi-center studies with minimal training.

To examine the efficacy and safety of modafinil on parkinsonism and excessive daytime sleepiness (EDS), as well as on negative symptoms and cognitive abilities in patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) in a randomized double-blind placebo-controlled 8-week study.Twenty-four male patients, who were aged 20-63 years and on stable dose of second generation antipsychotic medications and with a negative symptom score of ≥ 20 on the Positive and Negative Syndrome Scale (PANSS), were randomized into either the modafinil (n=12) or placebo (n=12) group. The modafinil group received flexible does of modafinil 50-200mg/day. Primary measurements were the Simpson-Angus Scale (SAS) for extrapyramidal side effects (EPS), the Epworth Sleepiness Scale (ESS), the PANSS and a neuropsychological (NP) test battery. Data were collected on Days 0, 14, 28, 42 and 56 for rating scales, and on Days 0, 28 and 56 for NP tests.Mixed model analyses showed a significant group-x-time interaction for total SAS scores (P0.006), with scores decreasing in the modafinil group but remaining the same in the placebo group. There were no significant group-x-time interactions for scores of ESS (total), PANSS (total, positive and negative), and NP tests (composite and domains) (all P's0.5). No significant adverse events were observed.The data suggest that modafinil was a safe adjunctive treatment which improved parkinsonian symptoms and signs in patients with schizophrenia or schizoaffective disorder. Further studies in larger samples and with longer study time are needed to test/confirm the beneficial effects of modafinil on motor function.

A century after Kraepelin, clinical scientists still debate whether the major functional psychoses, schizophrenia and bipolar illness, are separate disease entities or fall on opposite ends of a spectrum of severe psychopathology. In a study of control of hand-muscle force, patients with schizophrenia and bipolar affective disorder exhibited opposite asymmetries, with greater right-hand dyscontrol in schizophrenia, and greater left-hand dyscontrol in bipolar disorder. This suggests that there is greater pathological involvement of the dominant hemisphere in schizophrenia and of the non-dominant hemisphere in bipolar disorder.

Studies of extrapyramidal motor function in patients with schizophrenia have contributed to our understanding of the phenomenology and therapeutic outcome associated with neuroleptics. An increasing body of literature suggests that extrapyramidal motor abnormalities associated with schizophrenia may be linked to the pathophysiological mechanisms responsible for schizophrenia. Similarly, it has been documented that the extrapyramidal system may be involved in motor abnormalities in patients with Alzheimer's disease (AD). The present study was undertaken to examine motor function in schizophrenia and AD patients with psychosis. Quantitative instrumental procedures were used to examine rigidity, tremor, and bradykinesia in 13 neuroleptic-naive patients with schizophrenia, 13 AD patients with psychosis, and 26 age-comparable controls. Both schizophrenia and AD patients had significantly higher tremor and rigidity scores than did normal subjects. This comparative study of schizophrenia and AD patients with psychosis suggests that the effect of dementia in patients with psychosis is to prolong movement time, whereas abnormal parkinsonian postural tremor tends to be associated with psychosis in the absence of dementia.

It has been known for some time that patients with Parkinson's disease (PD) have difficulty executing simultaneous motor acts, yet the pathophysiology underlying this impairment remains uncertain. We examined the possibility that these dual-task deficits stem from defective sensorimotor mechanisms producing interference between the motor programs underlying the two tasks. Patients with PD and normal control subjects were tested on their ability to maintain steady-state force with one hand while performing a force-reaction time task with the other hand. Although performance was worse on the dual-task than on the single-task condition for both subject groups, only the patients with PD demonstrated significant interference between the two tasks. The interference across tasks improved in 87% of the patients with PD when tested after treatment with carbidopa/levodopa (Sinemet). These findings support the contention that, in patients with PD, disturbances in the execution of simultaneous motor performance may be due to sensorimotor disinhibition.

The primary purpose of this study was to examine motor physiology disturbances in a group of patients with untreated major depressive disorder using sensitive instrumental procedures. The secondary aim of the study was to examine the relationship of the affective symptom state to these motor assessments. The authors studied 40 individuals meeting DSM-IV criteria for unipolar major depressive disorder and 40 healthy comparison subjects. Electromechanical measures of force steadiness (FS), simple reaction time (RT), movement time (MT) and scaling of movement velocity to distance (velocity scaling, VS) were performed. The authors found that performance on the force steadiness, movement time, and velocity scaling measures was significantly poorer in the subjects with depression. There was no difference between the groups on the measure of reaction time. The force steadiness, reaction time, movement time, and velocity scaling scores were not associated with affective state. This study demonstrates that motor abnormalities suggestive of basal ganglia dysfunction occur in many patients with major depressive disorder, and that these abnormalities may exist in the absence of current psychotropic medication treatment. The finding of impaired movement time and velocity scaling in the presence of normal reaction time suggests a neuromotor or parkinsonian pathophysiology for slowness in depression.

Controlled trials provide critical tests of hypotheses generated by meta-analyses. Two recent meta-analyses have reported that gray matter volumes of schizophrenia and bipolar I patients differ in the amygdala, hippocampus, or perigenual anterior cingulate. The present magnetic resonance imaging study tested these hypotheses in a cross-sectional voxel-based morphometry (VBM) design of 17 chronic schizophrenia and 15 chronic bipolar patients and 21 healthy subjects matched for age, gender and duration of illness. Whole brain gray matter volume of both the schizophrenia and bipolar groups was smaller than among healthy control subjects. Regional voxel-wise comparisons showed that gray matter volume was smallest within frontal and temporal regions of both patient groups. Region of interest analyses found moderately large to large differences between schizophrenia and healthy subjects in the amygdala and hippocampus. There were no group differences in the perigenual anterior cingulate. When schizophrenia and bipolar groups were directly compared, the schizophrenia group showed smaller gray matter volumes in right subcortical regions involving the right hippocampus, putamen, and amygdala. The hippocampal and amygdala findings confirm predictions derived from recent meta-analyses. These structural abnormalities may be important factors in the differential manifestations of these two functional psychotic disorders.

There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

We evaluated 21 right-handed psychiatric patients with tardive dyskinesia (TD) for the presence and laterality of neuroleptic-induced tremor and rigidity. The goals of the study were to assess the frequency and coexistence of TD and neuroleptic-induced parkinsonism (NIP) using instrumental and clinical measurements and to evaluate the hypothesis that when TD and NIP coexisted in the same patient, they were more likely to appear in opposite limbs. Results indicated that a high percentage of TD patients had coexisting rigidity and tremor on the basis of both clinical ratings and instrumental procedures; however, only instrumental procedures were useful in identifying tremor and rigidity asymmetries. We found that TD and tremor or rigidity did not lateralize to opposite limbs, thus weakening the hypothesis that TD and NIP stemmed from reciprocal pathophysiological mechanisms.

Purpose Previous studies (e.g., G. Wulf, M. Höß, & W. Prinz, 1998; G. Wulf, B. Lauterbach, & T. Toole, 1999; for a review, see G. Wulf & W. Prinz, 2001) have reported that limb motor performance is enhanced when individuals adopt an external focus (focusing on the effect of the movement) versus an internal focus of attention (focusing on body parts such as the muscles of the hand). This study tested the hypothesis that the effects of attentional focus on limb performance would also occur in the oral-facial system. Method Two groups of 23 participants were administered both hand and tongue impulse force control tasks in which each group was randomly assigned either an internal or an external focus of attention. Participants were required to exert rapid pressure bursts to achieve a target force level of 20% of their maximal strength. Results Consistent with limb studies, findings revealed a significant advantage of an external focus (greater accuracy, less variability) for both the hand and tongue control tasks, as opposed to an internal focus of attention. Conclusions Results are discussed relative to a constrained-action theory of motor control and future application to speech motor learning.

Psychiatric phenotypes as currently defined are primarily the result of clinical consensus criteria rather than empirical research. We propose, and present initial proof of principle for, a novel approach to characterizing psychiatric phenotypes. We have termed our approach PhenoChipping, by analogy with, and borrowing paradigms and tools from, gene expression microarray studies (GeneChipping). A massive parallel profiling of cognitive and affective state is done with a PhenoChip composed of a battery of existing and new quantitative psychiatric rating scales, as well as hand neuromotor measures. We present preliminary data from 104 subjects, 72 with psychotic disorders (bipolar disorder-41, schizophrenia-17, schizoaffective disorder-14), and 32 normal controls. Microarray data analysis software and visualization tools were used to investigate: 1. relationships between phenotypic items ("phenes"), including with objective motor measures, and 2. relationships between subjects. Our analyses revealed phenotypic overlap among, as well as phenotypic heterogeneity within, the three major psychotic disorders studied. This approach may be useful in helping us move beyond current diagnostic classifications, and suggests a combinatorial building-block (Lego-like) structure underlies psychiatric syndromes. The adaptation of microarray informatic tools for phenotypic analysis readily facilitates direct integration with gene expression profiling of lymphocytes in the same individuals, a strategy for molecular biomarker identification. Empirically derived clusterings of (endo)phenotypes and of patients will better serve genetic, pharmacological, and imaging research, as well as clinical practice.

Monitoring drug-induced side effects is especially important for patients who undergo treatment with antipsychotic medications, as these drugs often produce extrapyramidal side effects (EPS) resulting in movement abnormalities similar to parkinsonism. Scientists have developed several objective laboratory tests to measure and research drug-induced movement disorders, but equipment and tests are complex and costly and have not become accepted in large-scale, multi-site clinical trials. The goals of this study were to test whether a simple handwriting measure can discriminate between individuals with psychotropic-induced parkinsonism, Parkinson's disease, and healthy individuals, and to examine some of the psychometric properties of the measure. We examined pen movement kinematics during cursive writing of a standard word in 13 patients with idiopathic Parkinson's disease (PD), 10 schizophrenia patients with drug-induced parkinsonism (SZ), and 12 normal healthy control participants (NC). Participants were instructed to write the word "hello" in cursive twice, at three vertical height scales. Software was used for data acquisition and analysis of vertical stroke velocities, velocity scaling, and smoothness. There were four important results from this study: (1) both SZ patients with drug-induced EPS and PD participants exhibited impaired movement velocities and velocity scaling; (2) performance on the velocity scaling measure distinguished drug-induced EPS from normal with 90% accuracy; (3) SZ, but not PD participants displayed abnormalities in movement smoothness; and (4) there was a positive correlation between age and magnitude of the velocity scaling deficit in PD participants. This study demonstrates that kinematic analyses of pen movements during handwriting may be useful in detecting and monitoring subtle changes in motor control related to the adverse effects of psychotropic medications.

This review summarizes the preclinical literature of the effects of methamphetamine (MA) on subcortical dopaminergic and GABAergic mechanisms underlying motor behavior with the goal of elucidating the clinical presentation of human MA-induced movement disorders. Acute and chronic MA exposure in laboratory animal can lead to a variety of motor dysfunctions including increased locomotor activity, stereotypies, diminished or enhanced response times, and parkinsonian-like features. With the exception of psychomotor impairment and hyperkinesia, MA-induced movement disorders are not well documented in humans. This review attempts to draw parallels between the animal and human changes in basal ganglia neurochemistry associated with MA exposure and offers explanations for why a parkinsonian phenotype is not apparent among individuals who use and abuse MA. Significant differences in the expression of neurotoxicity and presence of multiple environmental and pharmacologic confounds may account for the lack of a parkinsonian phenotype in humans despite evidence of altered dopamine function.

The ability of the left and right hemispheres to interact and cooperate in the processing of information is important for normal brain functioning. Some investigators have suggested that this cooperation in functioning occurs through a process called "metacontrol." Because studies have suggested that patients with schizophrenia may have problems with interhemispheric interaction, we considered that it could be informative to study such patients from the viewpoint of interhemispheric cooperation, and more specifically that of metacontrol. To do this we utilized an assessment procedure called the consonant-vowel-consonant (CVC) task, in which nonsense three-letter combinations (trigrams) are presented vertically to the left, right and both visual fields. The pattern of errors can be used to determine the type of processing the hemispheres use under the different conditions of presentation. Previous studies have shown that when trigram information is presented to both hemispheres, the left hemisphere appears to switch into a mode that more resembles right hemisphere processing, and we wished to determine if evidence for this switch in the mode of processing also occurred in a sample of patients with schizophrenia. To determine the specificity of any findings to schizophrenia, we also studied a group of patients with bipolar disorder. For the control and bipolar groups, our results showed the typical finding of superior processing in the right visual field (left hemisphere) over the left visual field, with presentation to both visual fields demonstrating a qualitative error pattern resembling that of the left visual field (right hemisphere). Patients with schizophrenia, however, did not demonstrate this switching into a right hemisphere mode upon bilateral presentation of the trigrams and instead seemed to show no switching, or actually switching into more of a left hemisphere mode. Our results suggest that patients with schizophrenia (but not bipolar disorder) may have abnormalities in the cooperative processing of information when it is presented to both hemispheres, and that this disturbance may reflect problems with metacontrol of hemispheric processing.

Background Evidence from the neuroimaging literature suggests that the basal ganglia plays an important role in the regulation of affect. This conclusion stems almost exclusively from group comparisons and it remains unclear whether previous findings can be confirmed from a longitudinal study of mood change. The aim of this study was to increase our understanding of the functional role of the basal ganglia and thalamus in relation to change in affect in patients with bipolar disorder. Methods Ten bipolar disorder subjects participated in a functional MRI study. We used a simple motor reaction time task to probe subcortical regions bilaterally. Subjects were scanned twice, once when their self-reported mood ratings indicated hypomania or euthymia and then again when they were in depressed states. Results Subjects in their euthymic or hypomanic states exhibited increased caudate activity bilaterally and the globus pallidus of the left hemisphere. Longitudinal analyses revealed a significant association between an increase in severity of depression and a decrease in activity in the external segment of the right globus pallidus. Conclusions Our findings suggest that the globus pallidus is less responsive during a simple motor task in the depressed compared to the normal or euthymic states in patients with bipolar disorder. These results are consistent with current physiologic models of basal ganglia circuitry in which an increase in caudate activity results in an increase in inhibitory GABAergic outflow to the external globus pallidus and subsequent decrease in thalamocortical excitation and may underlie the clinical manifestations of depression in bipolar disorder. Limitations The findings of this study need to be interpreted with caution as correlation coefficients may be overestimated in this small study sample.

From the very inception of the modern diagnostic scheme for psychotic disorders, abnormalities in motor function have been observed in these conditions. Despite convergence from multiple areas of research supporting the notion that multiple frontal-subcortical circuits regulate motor and limbic behavior, the precise relationship between motor abnormalities and psychopathology has not been elucidated. The goals of this study were to examine the prevalence of extrapyramidal signs (EPS) in first-episode schizophrenia patients and their relationships to three psychopathological dimensions (positive psychosis syndrome, negative syndrome, and disorganization). We assessed EPS using traditional observer-based as well as quantitative instrumental measures in 39 neuroleptic-naive first-episode schizophrenia subjects. Subjects were followed for 6 months after initiating antipsychotic treatment to examine the stability of motor-limbic relationships. Four main findings emerged from this study. First, depending on the measure used the prevalence of dyskinesia prior to treatment ranged from 13% to 20%. The prevalence of parkinsonism ranged from 18% to 28%. Second, severity of dyskinesia was associated with the positive psychotic syndrome; whereas parkinsonism was associated with the positive psychosis, negative syndrome and disorganization. Third, psychopathology improved significantly across all symptom dimensions following antipsychotic treatment, while EPS remained stable. This suggests that some motor abnormalities in schizophrenia may reflect trait characteristics. Fourth, abnormalities on the pre-treatment instrumental measure of parkinsonism predicted greater improvement on positive psychosis symptoms following treatment (p=0.008). Our findings support the notion that neuromotor disturbances may be a core feature of schizophrenia in a substantial proportion of patients and implicate multiple fronto-striatal circuits regulating limbic and neuromotor behavior in schizophrenia.

Structural neuroimaging studies have identified abnormalities in the basal ganglia in patients with bipolar disorder. Findings have been mixed with regard to affective state and have not elaborated on the role of medication on functional brain activity. The aims of the present study were to use functional magnetic resonance imaging (fMRI) to test whether depressed and manic bipolar disorder patients differ in terms of activity in cortical and subcortical brain areas and to examine the effects of psychotropic medication. Twenty-four bipolar disorder subjects and 13 healthy comparison subjects participated in an fMRI study of manual reaction time. Both manic and depressed subjects exhibited abnormally elevated blood oxygen level dependent BOLD responses in cortical and subcortical areas. Manic bipolar subjects had significantly higher BOLD responses in the left globus pallidus and significantly lower BOLD responses in the right globus pallidus compared with depressed bipolar patients. Correlational analyses revealed significant relationships between the severity of mania and activity within the globus pallidus and caudate. Patients off antipsychotic or mood-stabilizing medication exhibited significantly higher BOLD responses throughout the motor cortex, basal ganglia and thalamus compared with patients on these medications. These results suggest that affective state in bipolar disorder may be related to a disturbance of inhibitory regulation within the basal ganglia and that antipsychotics and/or mood stabilizers normalize cortical and subcortical hyperactivity.

The authors examined severity of dyskinesia in 119 men and 44 women, comparing by gender those with late-onset schizophrenia (LOS) versus early-onset schizophrenia (EOS). Women with LOS and men with EOS had more severe dyskinesia than men with LOS and women with EOS. Many factors, including the length of neuroleptic treatment, alcohol and smoking history, and menopausal status, may contribute to the severity of dyskinesia in older patients with schizophrenia.

Background: Motor retardation is a common feature of major depressive disorder having potential prognostic and etiopathological significance. According to DSM-IV, depressed patients who meet criteria for psychomotor retardation, must exhibit motor slowing of sufficient severity to be observed by others. However, overt presentations of motor slowing cannot distinguish slowness due to cognitive factors from slowness due to neuromotor disturbances. Methods: We examined cognitive and neuromotor aspects of motor slowing in 36 depressed patients to test the hypothesis that a significant proportion of patients exhibit motor programming disturbances in addition to psychomotor impairment. A novel instrumental technique was used to assess motor programming in terms of the subject’s ability to program movement velocity as a function of movement distance. A traditional psychomotor battery was combined with an instrumental measure of reaction time to assess the cognitive aspects of motor retardation. Results: The depressed patients exhibited significant impairment on the velocity scaling measure and longer reaction times compared with nondepressed controls. Approximately 40% of the patients demonstrated abnormal psychomotor function as measured by the traditional battery; whereas over 60% exhibited some form of motor slowing as measured by the instruments. Approximately 40% of the patients exhibited parkinsonian-like motor programming deficits. A five-factor model consisting of motor measures predicted diagnosis among bipolar and unipolar depressed patients with 100% accuracy. Limitations: The ability of motor measures to discriminate bipolar from unipolar patients must be viewed with caution considering the relatively small sample size of bipolar patients. Conclusions: These findings suggest that a subgroup of depressed patients exhibit motor retardation that is behaviorally similar to parkinsonian bradykinesia and may stem from a similar disruption within the basal ganglia.

The authors studied the risk of tardive dyskinesia for older patients in the early stages of treatment with typical neuroleptics.They examined the cumulative incidence of tardive dyskinesia 1, 3, 6, 9, and 12 months after the institution of neuroleptic therapy among 307 psychiatric outpatients over age 45. The patients' median dose was 68.4 mg/day of chlorpromazine equivalent.In the patients who had never received neuroleptics at baseline (N = 87), the mean cumulative incidence of tardive dyskinesia was 3.4% and 5.9% at 1 and 3 months, respectively. There was no significant difference in the 12-month cumulative incidence of tardive dyskinesia among patients who had been neuroleptic-naive at baseline (22.3%) and the 89 patients who had received neuroleptics before baseline for 1-30 days (24.6%); however, the 131 patients who had received neuroleptics before baseline for more than 30 days tended to have a greater cumulative 12-month incidence of tardive dyskinesia (36.9%).The risk of tardive dyskinesia in older outpatients is high, even with relatively short treatment with low doses of conventional neuroleptics.

Neuroleptics have revolutionized the treatment of schizophrenia and other psychoses since the early 1950s. Several adverse neurobiological effects are, however, associated with the long-term use of these agents. This article will review human and animal studies of these adverse effects, and also present some new data. Tardive dyskinesia (TD) is the most widely studied potentially persistent movement disorder resulting from long-term neuroleptic treatment, and several risk factors for TD development have been identified. Although drug-induced parkinsonism (DIP) usually disappears after the offending agent is withdrawn, a small portion of patients may have persistent parkinsonism. It is however, unclear if this is an aging-related effect. Persistent cognitive impairment associated with long-term use of typical neuroleptics has not been well documented. Atypical antipsychotics may produce improvement in cognitive performance in patients with chronic schizophrenia. MRI changes that are secondary to neuroleptics are possible, but have not yet been studied adequately. There is one unconfirmed report of neurofibrillary tangles associated with long-term neuroleptic use. A number of investigators have reported vacuous chewing movements, and neuropathologic changes following prolonged administration of neuroleptics in animals. We discuss the implications of the various reported adverse effects of long-term use of neuroleptics.

Differences in functioning between the two cerebral hemispheres have been reported for more than a century. In recent decades, issues related to lateralized dysfunction have been raised in psychiatric illnesses such as schizophrenia and bipolar disorder. In particular, evidence suggests that schizophrenia may be particularly associated with left hemisphere dysfunction and bipolar disorder with right hemisphere dysfunction. We discuss these issues, along with a conceptual framework for integrating hypotheses about the relationship between the major psychotic illnesses based on a two-dimensional continuum. We also present new findings from our study of motor asymmetry in older patients with psychosis that support this framework. Our results indicate that schizophrenia may be associated with left hemisphere pathology to a greater extent than right, whereas the reverse may occur in bipolar disorder.

1. 1. Serum-soluble interleukin-2 receptors (SIL-2Rs), a sign of immune activation, are increased in approximately 30% of schizophrenic subjects. 2. 2. In a recent publication the authors found that SIL-2Rs were particularly elevated in schizophrenic subjects with tardive dyskinesia (TD). 3. 3. This paper investigates the relationship between muscle force instability and SIL-2Rs in 32 schizophenic patients, 10 of whom were neuroleptic-naive. 4. 4. The authors hypothesized that there would be a positive correlation between increased levels of SIL-2Rs and muscle force instability. 5. 5. Serum SIL-2Rs and muscle force instability were positively correlated (r = 0.54, p < .001) in the schizophrenic patients, and this correlation held even for the subset of neurolepticnaive patients (r = .73, df 8, p = .016). 6. 6. These findings suggest that there is an important correlation between immune activation and muscle force instability in schizophrenic patients.

BackgroundControversy surrounds the relationship between tardive dyskinesia (TD) and symptoms of schizophrenia. While some studies reported that negative symptoms of schizophrenia may be a risk factor for TD, others reported a relationship between TD and positive symptoms.MethodEighty-four patients were studied, of whom 47 met criteria for TD. Clinical and instrumental procedures were used to increase the sensitivity of our assessments of the presence and severity of TD. Stepwise logistic and linear regression procedures were used to identify demographic variables, psychopathology, and motor parameters associated with the presence and severity of TD.ResultsA 3-factor model consisting of age, clinical tremor, and negative symptoms explained 25% of the variance in clinical TD severity. A 6-factor model consisting of female gender, instrumental and clinical measures of parkinsonism, positive, and negative symptoms explained 49% of the variance in severity of instrumentally derived dyskinesia.ConclusionsThese results suggest that the presence of TD may be associated with positive symptoms; that the severity of TD may be related to negative symptoms; and that the relationship between negative symptoms and TD severity may be influenced by the presence of parkinsonism.

The voluntary motor disturbances found among many schizophrenic patients consist of motor incoordination, disturbed pursuit tracking, difficulty following movement sequences, desynchronized tapping, and a myriad of neurologic soft signs. The problem with many of these observations is that it is extremely difficult to distinguish movement disorders related to neuroleptic treatment from those that may have occurred spontaneously. The aim of the present study was to examine potential disturbances in the voluntary control of steady-state force in neuroleptic-naive schizophrenic patients and normal comparison subjects. Twenty-one patients and 21 age- and gender-matched comparison subjects were studied. Spectral analyses of hand force instability revealed a significant difference between patients and comparison subjects. In 52 of the patients, the disturbance in the control of force exceeded the 95th percentile of the comparison mean. Degree of force instability was correlated with positive but not negative symptoms of schizophrenia. These findings suggest that schizophrenic patients may exhibit a disturbance in the control of muscle force that cannot be attributed to the neuroleptic effects of antipsychotic medication. The pattern of disruption, characterized by abnormal spectral energy within the 1.5 to 3.0 Hz range, suggests a motor disturbance that resembles tardive dyskinesia. Implicit within these findings of neuroleptic naive patients is the possibility that disturbances in the control of isometric force may represent spontaneous dyskinesia.

Objective Previous studies in schizophrenia have identified abnormalities involving the basal ganglia, but the contribution of neuroleptics to the motor system abnormalities in schizophrenia is usually a confounding factor. This study addressed the issue of whether parkinsonism, a reflection of dopaminergic hypofunction, occurs in schizophrenia per se. Method Clinical ratings and quantitative instrumental measures of parkinsonian rigidity, tremor, and bradykinesia were obtained in 24 neuroleptic-naive schizophrenic patients and 24 age- and gender-matched comparison subjects. Results According to the clinical ratings, 21% of the schizophrenic patients had rigidity and 12% had bradykinesia, in contrast to none of the normal comparison subjects. With the use of instrumental measures, rigidity and tremor were observed in 29% and 37%, respectively, of the schizophrenic patients, compared to 4% and none in the normal comparison group. The schizophrenic patients also exhibited greater right-side than left-side parkinsonism. Conclusions The findings suggest that extrapyramidal motor signs may be part of schizophrenia proper and that some patients with schizophrenia have left striatal hypodopaminergia unrelated to neuroleptic treatment.