Michael P. Caligiuri

Lower Incidence of Tardive Dyskinesia with Risperidone Compared with Haloperidol in Older Patients

OBJECTIVE: To compare the 9‐month cumulative incidence of tardive dyskinesia (TD) with risperidone to that with haloperidol in older patients.

Motor and cognitive aspects of motor retardation in depression.

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 subjects 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.

Identification of blood biomarkers for psychosis using convergent functional genomics.

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.

An fMRI study of affective state and medication on cortical and subcortical brain regions during motor performance in bipolar disorder

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.

Antipsychotic-Induced movement disorders in the elderly: epidemiology and treatment recommendations.

We reviewed the epidemiological aspects of antipsychotic-induced movement disorders as they pertain to older patients. The incidence and prevalence of drug-induced parkinsonism and tardive dyskinesia (TD) are significantly greater in the older patient than in the younger patient whereas akathisia seems to occur evenly across the age spectrum and dystonia is uncommon among older patients. The literature on risk factors associated with treatment-emergent movement disorders is highly variable. Treatment practices vary across the age range and the interaction between age and antipsychotic dosage confounds our understanding of the relative importance of treatment-related risk factors. However, there is general agreement that pre-existing extrapyramidal signs (EPS) increase the vulnerability of the patient to developing significant drug-induced movement disorders. Elderly patients with dementia are at greater risk than patients without dementia for persistent drug-induced EPS.Management of drug-induced movement disorders in the older patient requires careful consideration of the contraindications imposed by such agents as anticholinergics and β-blockers. At present, well-controlled double-blind studies of second-generation antipsychotics such as clozapine, risperidone, olanzapine or quetiapine for reducing the risk of treatment-emergent movement disorders in the elderly have not been published. However, open-label studies of atypical antipsychotics demonstrate a markedly lower incidence of both EPS and TD compared with conventional antipsychotic treatment in the elderly. There is emerging literature in support of atypical antipsychotics for the treatment of existing drug-induced movement disorders. More controversial is the use of adjunctive antioxidants in newly treated patients who are vulnerable to drug-induced movement disorders. While the evidence is mixed in support of antioxidants for the treatment of TD, the possibility remains that prophylactic use of antioxidants may help reduce the incidence of TD.The development of a drug-induced movement disorder often reduces the quality of life in an elderly patient. Effective pharmacological management requires cooperation from the patient and family, which can be fostered early in the patient’s care through proper informed consent. The risks and benefits of antipsychotic treatment in the elderly patient need to be communicated to the patient and family. At the present time, there is no consistently effective treatment for patients with TD once it develops. Therefore, attention should focus on its prevention and close monitoring.

The influence of speaking rate on articulatory hypokinesia in Parkinsonian dysarthria

This study addressed the question of whether or not speaking rate influences articulatory hypokinesia in dysarthria associated with Parkinsons disease. Analyses of parkinsonian speech samples revealed mean speaking rates consistent with normal controls. Thus, speaking rate was not abnormal overall in this group of dysarthric subjects. Kinematic analyses of labial displacement amplitude, peak instantaneous velocity, and movement time were made during repetitive syllable production spoken at two speaking rates: 3-5 syllables/sec and 5-7 syllables/sec. The results suggested that labial movements were normal at the slower of the two speaking rates. Conversely, labial movements became hypokinetic as speaking rate increased to the rate consistent with conversational speech. These findings provide a physiologic basis for the perception of hypokinetic dysarthria in Parkinsons disease and suggest that speaking rate may be an important control variable contributing to articulatory hypokinesia in Parkinsons disease. Moreover, these findings provide quantitative evidence that articulatory hypokinesia plays a dominant role in the perception of parkinsonian dysarthria.

Relationship of neuromotor disturbances to psychosis symptoms in first-episode neuroleptic-naïve schizophrenia patients

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.

A disturbance in the control of muscle force in neuroleptic-naive schizophrenic patients

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.

Extrapyramidal Motor Signs in Clinically Diagnosed Alzheimer Disease

Summary:We reviewed clinical case series published over a 10-year period addressing the cross-sectional frequency, incidence, and diagnostic and prognostic significance of extrapyramidal signs (EPS) in Alzheimer disease (AD). The review was prompted by recent reports of Lewy body (LB) pathology in the brains of many AD patients and the association of LB pathology with clinical parkinsonism in AD. In the clinical case series reviewed, we evaluated several possible determinants of prevalent EPS, including neuroleptic use, EPS assessment technique, and dementia severity. Neuroleptics were a well recognized cause of parkinsonism in these reports, though some failed to document the frequency of neuroleptic use. Assessment methods were also important: Studies using structured clinical research scales to rate EPS reported higher frequencies than studies employing routine neurological examination. The relationship between parkinsonism and dementia severity was complex. Some studies found bradykinesia, facial masking, and parkinsonian postural changes even in mildly demented, neuroleptic-naive AD patients. Rigidity, on the other hand, became increasingly common as dementia progressed. AD patients with EPS showed faster cognitive and functional decline and earlier death than those without EPS, even after consideration of differences in initial dementia severity. In the differential diagnosis of dementia with parkinsonism, LB disease in its various forms, including AD with LB, is the principal diagnostic consideration. Future studies of parkinsonism in AD should employ standardized clinical rating scales and should exclude patients on neuroleptics or analyze their results separately. Investigators should report frequencies for individual parkinsonian signs in addition to the overall prevalence of EPS to facilitate meaningful comparisons across studies.

Incidence and predictors of drug-induced parkinsonism in older psychiatric patients treated with very low doses of neuroleptics.

The available literature suggests that a sizable proportion of patients placed on neuroleptics develop acute and subacute extrapyramidal side effects, including neuroleptic-induced parkinsonism (NIP). The presence of mild, spontaneous extrapyramidal signs in the elderly makes it difficult to accurately estimate the incidence of NIP in this subgroup of patients. We examined the incidence of NIP in 56 older, newly medicated, psychiatric patients. Fifteen age-comparable, unmedicated psychiatric patients underwent 2 assessments to estimate natural fluctuation in extrapyramidal signs, and 49 normal, healthy, elderly individuals were also studied to establish age-comparable norms for the assessment of parkinsonism. Potential pretreatment predictor variables included instrumental measures of motor function, age, cognitive status, and psychiatric diagnosis. After controlling for spontaneous parkinsonism, 32% of patients met strict criteria for NIP after receiving an average of 43 mg/day chlorpromazine equivalents of a typical neuroleptic. Factors contributing to the development of NIP included older age, instrumentally derived tremor, baseline extrapyramidal signs, type of neuroleptic, and severity of dementia. The use of risperidone in a small subsample was not associated with NIP. These findings indicate that even after controlling for spontaneous extrapyramidal signs at baseline and their natural fluctuations, there is a substantial risk of NIP in older patients who are treated with very low doses of typical neuroleptics.