Early extrapyramidal side-effects as risk factors for later tardive dyskinesia: a prospective study

OBJECTIVE: To determine whether acute neuroleptic-induced parkinsonism and akathisia were risk factors for the later development of tardive dyskinesia (TD) in patients on typical neuroleptics. METHOD: Of 100 subjects examined for parkinsonism and akathisia after the initiation of typical neuroleptic medication, 78 were followed up for TD after a mean 41.2 months. RESULTS: Nine (11.5%) subjects were diagnosed with TD, predominantly manifesting as oro-facial dyskinesia. They had greater severity of parkinsonism and akathisia at baseline, and a larger neuroleptic load, than those who did not develop TD. On regression analyses, parkinsonism at baseline was a significant predictor of later TD. Examined independently of parkinsonism, akathisia severity at 2 weeks was also a significant predictor of later TD. CONCLUSIONS: Acute drug-induced parkinsonism and akathisia are both predictors of TD, with parkinsonism having greater predictive value. Acute and tardive extrapyramidal syndromes may share vulnerability factors.     

Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients

OBJECTIVE: Since most of the world's schizophrenia patients are treated with conventional antipsychotics, the authors evaluated various methods for establishing the prevalence of neuroleptic-induced movement disorders in these patients. METHOD: DSM-IV criteria and established score thresholds on a movement disorder rating scale were used to identify cases of neuroleptic-induced movement disorder in a representative Estonian patient sample of 99 chronic institutionalized schizophrenia patients, 18-65 years old, treated with conventional neuroleptics (79.8%) or clozapine (20.2%). RESULTS: Neuroleptic-induced movement disorders according to DSM-IV criteria were found in 61.6% of the group: 31.3% had neuroleptic-induced akathisia, 23.2% had neuroleptic-induced parkinsonism, and 32.3% had neuroleptic-induced tardive dyskinesia. Prevalence rates for akathisia and tardive dyskinesia were similar when either DSM-IV criteria or rating scale scores were used, but the prevalence rate for parkinsonism was much lower per DSM-IV criteria than according to rating scale score. CONCLUSIONS: Nearly two-thirds of chronic schizophrenia patients suffered from a neuroleptic-induced movement disorder. Globally, extrapyramidal adverse effects still impose a huge burden on the majority of neuroleptic-treated individuals with schizophrenia. The discrepancy between the standard identification methods for neuroleptic-induced movement disorder indicate the need for further research.     

Recognition and management of acute neuroleptic-induced extrapyramidal motor and mental syndromes

After nearly 50 years of therapeutic application of neuroleptics, diagnosis and classification of neuroleptic-induced extrapyramidal syndromes still concentrate on their "neurological" (motor) aspects. Psychiatric (mental) aspects are in general - if at all - regarded as "secondary" to motor symptoms. Psychiatric side effects of neuroleptics (including psychotic exacerbations during neuroleptic treatment) have, however, anecdotally been reported since 1954 but never developed into a systematic classification. Accordingly, psychiatric manifestations of extrapyramidal side effects frequently are overlooked, misdiagnosed as psychotic deteriorations and treated by increased dosing of neuroleptics instead anticholinergics, which in addition are falsely suspected of bearing a high addictive potential and the risk of development of tardive dyskinesia. It is suggested that neuroleptic-induced basal ganglia dysfunction results in motor as well as mental extrapyramidal side effects, whose recognition and management is essential to achieve better tolerability of and thereby compliance with neuroleptic treatment.     

Smoking and movement disorders in psychiatric patients.

Previous studies have suggested that tardive dyskinesia may occur more frequently in patients who smoke. Further evidence of an interaction between smoking and movement disorders includes the low lifetime exposure to cigarettes found in Parkinson's disease patients. In this study 126 patients with chronic psychiatric illnesses were blindly evaluated for tardive dyskinesia, neuroleptic-induced parkinsonism, and akathisia. Patients who smoked received significantly higher doses of neuroleptics but did not have significantly more frequent or more severe tardive dyskinesia or parkinsonism. Female smokers did have significantly more akathisia. These results are discussed with regard to interactions between smoking, central dopaminergic tone, and the psychopathology of extrapyramidal syndromes. The effect of smoking on neuroleptic blood levels as well as clinical symptomatology is also discussed.     

Changes in extrapyramidal symptoms following anticholinergic drug withdrawal

An antiparkinson drug (APK) withdrawal study was carried out in 34 schizophrenic outpatients on maintenance neuroleptics. Sixty-five percent of patients were without major complaints after 2 weeks of APK discontinuation, while 35% reported adverse effects including extrapyramidal, autonomic, and behavioral symptoms. Male patients and those on higher diethazine doses before withdrawal reported more complaints. Ratings showed significant increases of parkinsonism, as well as dyskinesia following APK withdrawal. No clinical evidence was obtained in support of the notion of cholinergic hypersensitivity in patients showing "tremors" at baseline.     

Caudate hyperintensities in elderly depressed patients with neuroleptic-induced parkinsonism.

Elderly patients are particularly sensitive to the neurologic side effects of psychotropic medications. This increased sensitivity may be related to brain structural changes associated with aging. In this pilot study, the authors report on the occurrence of caudate hyperintensities, using brain magnetic resonance imaging, in seven elderly depressed subjects who developed neuroleptic-induced parkinsonism. Caudate hyperintensities were not observed in any of the seven healthy elderly controls examined. These results suggest that caudate hyperintensities may render some elderly depressed patients susceptible to neuroleptic-induced parkinsonism.     

Drug induced parkinsonism

Journal of Neurology - The use of neuroleptics as psychotherapeutic agents has resulted in extrapyramidal syndromes including parkinsonism. This specific drug-induced parkinsonism (DIP) mimics...     

Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.

Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.     

The impact of neuroleptic dosage and extrapyramidal side effects on schizophrenic basic symptoms

The impact of neuroleptic medication and extrapyramidal symptoms on abnormal subjective experiences in schizophrenia, also termed basic symptoms, as assessed with the Frankfurt Complaint Questionnaire (FCQ) was investigated in 40 schizophrenic patients medicated with conventional neuroleptics. Basic symptoms are thought to reflect the subjective side of schizophrenic vulnerability and to underlie schizophrenic symptomatology. It was expected that basic symptoms would inversely correlate with chlorpromazine equivalents, since neuroleptics not only improve acute schizophrenic symptoms but also have prophylactic properties. However, a significant positive correlation with neuroleptic dosage and extrapyramidal symptoms emerged, suggesting that basic symptoms as operationalized in the FCQ partly reflect neuroleptic-induced deficits. The results remained unchanged when global psychopathology was controlled for. In line with previous research, basic symptoms correlated with thought disorder but not with positive symptoms. However, when the effects of neuroleptic-induced disturbances were controlled for, thought disorder also insignificantly correlated with basic symptoms. Our findings confirm previous results that question the construct validity of the FCQ. Moreover, the need to control for confounding variables (such as medication) is emphasized by comparing different psychiatric groups.     

Dystonia in untreated parkinsonism

While parkinsonism and dystonia generally are distinct clinical syndromes, both may be prominent features even prior to the use of antiparkinsonian medications. In 10 patients with typical parkinsonism, coincident dystonic features included neck, upper extremity, oromandibular, unilateral upper-lower extremity, and unilateral foot dystonia. Six patients were first affected before the age of 45. For some, dystonia preceded parkinsonism (for 1/2 to 20 years). Limb symptoms tended to be unilateral; in seven patients, parkinsonism also was limited to that side. While levodopa was adequate for improvement of parkinsonism, dystonic symptoms benefited from the combination of levodopa with a dopaminergic ergot. The dystonic features (which also can result from parkinsonian therapy) often add pain and disability to the deficits in parkinsonism. The coexistence of dystonia may constitute a distinctive syndrome of parkinsonism and points to possible etiologic mechanisms shared by these two extrapyramidal disorders.     

Use of neuroleptic-induced extrapyramidal symptoms to predict future vulnerability to side effects.

OBJECTIVE: Susceptibility to neuroleptic-induced extrapyramidal syndromes varies widely, even within age and sex subgroups. Individual vulnerability to extrapyramidal syndromes has been assumed to explain this, but the utility of past history for predicting future occurrence of extrapyramidal syndromes has not been studied extensively. This investigation was undertaken to determine whether patients' previous histories of extrapyramidal syndromes predict future episodes of extrapyramidal syndromes and to compare the importance of this predictive factor with patient age, sex, neuroleptic dose, and anticholinergic dose as predictors of extrapyramidal syndromes. METHODS: The charts of 62 schizophrenic patients with multiple neuroleptic treatment episodes were reviewed. Extrapyramidal syndromes, neuroleptic drug doses, and anticholinergic drug doses during the first 21 days of each treatment episode were recorded. RESULTS: Previous extrapyramidal syndromes correctly predicted extrapyramidal syndromes in subsequent treatments for 84% of the patients. Variations in neuroleptic potency, neuroleptic dose, and anticholinergic dose partially explained incorrect predictions. CONCLUSIONS: These results support the hypothesis that patients with a history of extrapyramidal syndromes are at greater risk for future extrapyramidal syndromes. If confirmed, these results strongly support individual susceptibility as a major predictor of extrapyramidal syndromes and indicate that prophylaxis of extrapyramidal syndromes should be considered for patients who have previously suffered extrapyramidal syndromes from similarly prescribed neuroleptic therapy.     

Prospective study of neuroleptic-induced dystonia in mania and schizophrenia.

OBJECTIVE: The authors' goal was to conduct a prospective study comparing the rate of occurrence of neuroleptic-induced dystonia in a group of consecutively admitted manic and schizophrenic patients receiving typical inpatient treatment from several clinicians. METHOD: All patients met the following criteria: 1) male sex, 2) age between 17 and 45 years, 3) definite diagnosis of mania or schizophrenia according to Research Diagnostic Criteria, 4) no exposure to neuroleptics during the past month, 5) absence of past or family history of a neurodegenerative disorder with extrapyramidal symptoms. All treatment decisions were left to the treating clinicians. Fifty patients with mania and 33 with schizophrenia were included in the study. Most of these patients received high-potency neuroleptics, but the specific neuroleptic used varied in the two groups. RESULTS: Twelve (24%) of the patients with mania and five (15%) of the patients with schizophrenia developed acute dystonia. Manic patients received significantly higher peak doses of neuroleptics during the risk period for dystonia. Stepwise multiple regression analysis revealed that the peak neuroleptic dose and age were most strongly related to the occurrence of dystonia. CONCLUSIONS: This prospective study failed to support the retrospective finding of another study that acute dystonia occurred more often in manic patients than in patients with nonparanoid schizophrenia. The authors conclude that there is a need for carefully controlled prospective studies with larger groups of patients.     

Psychiatric admissions due to adverse drug reactions

This is a report of the findings of a 6-year study of hospitalizations caused by adverse psychiatric reactions to prescribed medications. Of 15,800 consecutive psychiatric admissions to two university hospitals, 112 (0.7%) were caused by adverse reactions to medications. In 67% of cases these admissions were due to extrapyramidal symptoms such as parkinsonism and/or akathisia, and coexisting neuroleptic-related depression. In 25% the admitting diagnosis was drug-induced delirium or psychosis; one third of these patients suffered from Parkinson's disease and had been treated with a combination of two or more antiparkinsonian agents. Older age, polydrug therapy, and the parenteral administration of neuroleptics at high dosages were important risk factors for severe adverse drug reactions leading to hospitalization.     

Susceptibility to neuroleptic-induced parkinsonism--age and increased substantia nigra echogenicity as putative risk factors.

OBJECTIVE: Patients treated by neuroleptics often develop neuroleptic-induced parkinsonism (NIP) to a varying extent. The reasons for this are discussed controversially in the literature. Previous transcranial sonography (TCS) findings of the substantia nigra (SN) in patients with idiopathic Parkinson's disease suggest a correlation of echogenicity with nigrostriatal dysfunction. METHOD: One hundred psychiatric patients receiving neuroleptics were included. They underwent clinical examination for NIP (Simpson and Angus-scale) and, independently, TCS of the SN. History of smoking habits and medication were taken from the patient's chart. RESULTS: We found a significant positive association of the prevalence of NIP with age (P < 0.01) and the echogenic area of the SN (P < 0.05). Neither type nor dosage of the neuroleptics was found to have any significant impact on the occurrence of NIP. Smokers displayed lower prevalence of NIP (P < 0.05) and lower EPS scores (P < 0.01). CONCLUSIONS: These findings suggest that age and increased size of SN echogenicity are possible risk factors for NIP. In contrast, smoking seems to have a certain protecting effect.     

Measurement of anticholinergic effects of psychotropic drugs in humans

Psychotropic drugs are often liable to unwanted anticholinergic effects that reduce tolerance and compliance. Especially, in certain patient groups, such as elderly patients, anticholinergic adverse effects may be hazardous. There are also occasions in therapy when antimuscarinic activity is desired, e. g. in the treatment of neuroleptic-induced extrapyramidal symptoms with biperiden and other potent anticholinergic drugs. In this review, we describe various techniques to evaluate the anticholinergic influences of psychotropic drugs in vivo and also provide examples of previous human studies where these methods have been applied. By combining subjective ratings of anticholinergic effects to in vitro measurements of antimuscarinic activity in blood, as well as the functional state of salivary glands, sweat glands, heart and eye, a researcher can obtain a detailed anticholinergic profile of the drug in question, or a clinician can estimate the anticholinergic burden of his/her psychiatric patient who often uses multiple medications.     

Acute extrapyramidal syndromes in neuroleptic-treated elders: a pilot study.

The incidence, morbidity, and risk factors for acute extrapyramidal syndromes (EPS) such as akathisia and drug-induced parkinsonism (DIP) in neuroleptic-treated elders have not been systematically explored. This study presents data on 17 elderly patients who were prospectively examined for up to 4 weeks for acute EPS, functional and cognitive status, and behavioral disturbances. Seventy-one percent of subjects developed DIP, and 18% developed akathisia. Predictors of DIP included pre-neuroleptic treatment parkinsonian signs and neuroleptic dose, despite use of low doses of neuroleptics. Development of acute EPS was associated with failure to improve behaviorally. New-onset urinary incontinence was the most common functional abnormality.     

Neuroleptic and anticholinergic drug use in Chinese patients with schizophrenia resident in a state psychiatric hospital in Singapore

OBJECTIVE: The objective of this study was to survey the prescribing pattern in Chinese patients with chronic schizophrenia in a state mental hospital in Singapore, and to compare our findings with those of surveys of Chinese patients in other countries. METHOD: We surveyed the use of neuroleptic and anticholinergic agents among Chinese patients with chronic schizophrenia (n = 534) in a state mental hospital in Singapore. RESULTS: Fifty-nine per cent of the patients received two or more neuroleptics (median daily dose of 400 mg chlorpromazine equivalents, range 50-2875 mg). There were no differences in gender distribution between those prescribed multiple neuroleptics as against an older group of those receiving none or only one neuroleptic medication. Sixty-six per cent of the patients were receiving depot neuroleptics, with more than half of these subjects also receiving additional oral neuroleptics. Patients who were prescribed multiple neuroleptics received significantly higher total doses than those receiving just one neuroleptic. Only 1% of patients were prescribed an atypical neuroleptic. Sixty-five per cent of patients were prescribed an anticholinergic agent. Those prescribed anticholinergic agents were younger, in receipt of higher doses of neuroleptic medications and had lower Simpson-Angus scores for extrapyramidal side-effects. CONCLUSIONS: The pervasive use of multiple typical neuroleptics, marked underutilisation of atypical neuroleptics, and the lack of anticholinergic medication in patients who might benefit from such treatment are issues of substantial concern, warranting action in both psychiatry practice and mental health policy.     

Phenomenology and therapy of neuroleptic-induced akathisia--a review of the literature

The neuroleptic-induced akathisia (NIA) often appears as a side effect of neuroleptic therapy in psychotic individuals. It can accompany or outlive the period of neuroleptic treatment. Besides the objective symptoms of motor restlessness it is especially the subjective symptoms and complaints as inner restlessness, anxiety, and depression, which cause severe annoyance or even torment patients. Exacerbations of disease symptoms treated with neuroleptics can occur. After outlining development of the concept of akathisia and of the knowledge of NIA some relevant findings in the field of NIA, especially in respect to their clinical pictures and their connections to related neuroleptic-induced side effects, are discussed. Development and present stand of treatment of NIA are described. Treatment with betablockers plays a central role. Pathophysiological aspects are touched in context with therapeutical considerations. The current state of knowledge of NIA allows a better understanding of pathophysiology in neuroleptic side effects in general, enables an almost sufficient treatment of NIA with betablockers, demonstrates the necessity of responsible and cautious use of neuroleptics by physicians and the necessity of careful guidance of such patients who are treated with neuroleptics.     

Psychotropic drug use and polypharmacy in a general hospital

This paper presents the usage of psychotropic drugs by all general inpatients of a Boston teaching and referral hospital on a randomly chosen weekday. Of all surveyed inpatients, 42.8% were receiving at least one psychotropic medication. Sleep medications were the most frequently prescribed class of psychotropic drugs and flurazepam was the most commonly prescribed of all drugs. Phenothiazine and neuroleptics were given to control agitation, pain, or nausea, rather than psychosis. Antidepressants were prescribed without notated justification in the medical record, and if given for depression, were underdosed. Diazepam was the most frequently prescribed antianxiety drug and was the most frequently prescribed psychotropic drug after flurazepam. Psychotropic drug polypharmacy was common, with the average patient receiving seven different drugs. Remedial approaches to this widespread problem are recommended.