• Fifty-six prevalence surveys of tardive dyskinesia (TD) in neuroleptic-treated patients are reviewed, yielding an average prevalence of 20% as compared with 5% prevalence of "spontaneous" dyskinesia in 19 samples of untreated individuals. Reported prevalence has increased during the past two decades and is not attributable simply to the more widespread use of rating scales. Controlled studies of a variety of risk factors are reviewed and suggest that advancing age and, to a lesser extent, female sex are the two variables most consistently associated with increased prevalence. There are relatively few data supporting the assumption that the risk of TD development continues to increase with increasing neuroleptic exposure, CNS dysfunction, or exposure to antiparkinsonism medication.

Tardive dyskinesia: prevalence and risk factors, 1959 to 1979.

The clinical use of antipsychotic agents may be enhanced by considering their dose-effect characteristics. In particular, assessment of immediate and later follow-up treatment of psychotic patients (1) indicates that moderate doses are adequate for most patients, (2) fails to support the utility of unusually high doses, and (3) even suggests the existence of a biphasic relationship of antipsychotic efficacy to dose of neuroleptics and possibly to plasma concentrations of the drugs as well. Trends toward lesser overall clinical benefits of high doses may reflect untoward extrapyramidal or other central nervous system effects leading to behavioral and cognitive symptoms. Thus, moderate doses of neuroleptics appear, on average, to be about as effective as, and probably safer than, the larger doses that have been popular in the United States in recent years.

Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses.

In the treatment of chronic schizophrenia, there are risks associated with both neuroleptic maintenance (eg, tardive dyskinesia) and neuroleptic withdrawal (eg, psychotic exacerbation or relapse). We reviewed 66 studies on neuroleptic withdrawal involving 4365 patients with schizophrenia. The mean cumulative relapse rate was 53% in patients withdrawn from neuroleptic therapy and 16% in those maintained on neuroleptic therapy over a mean follow-up period of 9.7 months. The relapse rate was positively associated with length of follow-up. Predictors of relapse reported in individual studies included younger age, higher baseline neuroleptic dosage, and shorter length of hospitalization. Adverse effects of neuroleptic withdrawal other than relapse were usually mild and transient. The risk-benefit ratio of neuroleptic maintenance vs withdrawal should be assessed carefully in individual patients. A slow taper to the lowest effective dosage may be the preferred strategy in many patients.

Neuroleptic withdrawal in schizophrenic patients. A review of the literature.

It is not widely recognized that antipsychotic drugs can cause late-onset and persistent dystonia. This dystonia, which we call tardive dystonia, is to be distinguished from acute dystonic reactions, which are transient, and from classic tardive dyskinesia, which is a choreic disorder that predominantly affects the oral region. We present 42 patients with tardive dystonia. The age of onset of dystonia was 13 to 60 years. Symptoms began after 3 days to 11 years of antipsychotic therapy. Younger patients tended to have more generalized dystonia. In a few patients, spontaneous remission occurred, but dystonia persisted for years in most. Therapy was rarely a complete success. The most frequently helpful medications were tetrabenazine (68% of patients improved) and anticholinergics (39% improved).

Tardive dystonia Late‐onset and persistent dystonia caused by antipsychotic drugs

• Advancing age is one of the few factors suggested to predict increased risk of tardive dyskinesias (TDs). By pooling and reanalyzing available epidemiological data, we found strong linear correlations between ages ( prevalences and severity of TD, while neither increased significantly after age 70 years. There was also a strong inverse correlation between rates of spontaneous remission of TD and age ( 80 years); TD in those younger than 60 years improved over three times as often as in older patients. These correlations are not readily explained by the duration of previous exposure to neuroleptic drugs and may reflect increased sensitivity of the aging brain to them. These observations support caution in the prolonged use of neuroleptics in patients older than age 50 years but encourage optimism for eventual spontaneous remission of TD in young adults.

Changes in Prevalence, Severity, and Recovery in Tardive Dyskinesia With Age

A systematic clinical study of certain defined types of `extra-pyramidal' motor phenomena was carried out in a population of 63 chronic hospitalized schizophrenics who had been treated with trifluoperazine for periods ranging from 3 to 13 years. Tremor was found in 88 per cent, muscular rigidity in 68 per cent, choreiform dyskinesia in 56 per cent, and motor restlessness in 38 per cent. The clinical data were submitted to factor analysis in order to identify the principal patterns of motor disorder affecting these patients. Sex, age, state of dentition, as well as phenothiazine and anti-parkinsonism drug treatment variables were then studied in relation to the distributions of the motor disorders suggested by factor analysis.

Factor 1, which accounted for 32.5 per cent of the variance, represented restlessness of the trunk and limbs. The distribution of this disorder in the population was not affected by any of the personal and treatment variables studied.

Factor 2 accounted for 19.1 per cent of the variance and represented tremor and rigidity of the upper limbs and facial musculature. This disorder was significantly more common in older patients.

Factor 3 was bipolar and contributed 13.0 per cent to the variance. It suggested a disorder of the tongue, lips and jaw characterized by choreiform movements at one pole negatively correlated with tremor at the other pole. Chorea was more common and tremor less common in women than in men. For men, though not women, chorea was associated with a low total dose of phenothiazine and tremor with a high total dose.

The usefulness of this method and the implications of our results are discussed, particularly with respect to choreiform disorders which may be irreversible.

Extrapyramidal disorders after prolonged phenothiazine therapy.

Sixty-two chronic schizophrenics in hospital were studied. There were 32 male and 30 female patients; their mean ages were 53.6 years and 60.4 years respectively. They had all been on regular phenothiazines, principally trifluoperazine, for a mean of 9.4 years.

Placebo capsules were substituted randomly for 32 patients. Within the 16 drug-free weeks that followed, 9 (28 per cent) patients relapsed sufficiently to require reinstatement on active phenothiazines. The mean drug-free period for those 9 patients was 5 weeks. They were significantly younger, had consumed larger quantities of phenothiazines over the years, and were originally receiving larger daily doses of trifluoperazine than the 23 patients who did not relapse.

The patients were rated for the three main extra-pyramidal syndromes—motor restlessness parkinsonian rigidity and tremor and oral dyskinesia-tremor, before and after trifluoperazine was withdrawn. The mean drug-free period was 16 weeks. Comparisons were made between before and after ratings, as well as between placebo and control trifluoperazine groups. Parkinsonian rigidity and tremor, and oral-dyskinesia-tremor did not appreciably change in the placebo or control groups. Motor restlessness worsened significantly in the placebo, but not the trifluoperazine group. Of the 23 placebo patients who were without trifluoperazine for 16 weeks, 8 remained free from motor restlessness, 1 patient continued unchanged, 3 patients improved, 6 patients became worse, and 5 patients developed the disorder for the first time. There was no significant difference in any of the variables tested between the patients who deteriorated and those who remained the same or improved.

Trifluoperazine withdrawal, in this study, was therefore followed by a psychiatric relapse in 28 per cent of the patients, persistence of parkinsonian rigidity and tremor and oral dyskinesia-tremor, and worsening of motor restlessness. The implications of these findings are discussed.

H. I. Hershon

Papers

Extrapyramidal disorders after prolonged phenothiazine therapy.

Persistence of Extra-pyramidal Disorders and Psychiatric Relapse after Withdrawal of Long-Term Phenothiazine Therapy