Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications. Results of the Yale Tardive Dyskinesia Study.

OBJECTIVES: To describe the incidence of tardive dyskinesia (TD) in the Yale TD Study and to identify demographic, treatment, and clinical risk factors for TD occurrence. DESIGN: An ongoing prospective cohort study in which subjects have been examined every 6 months since 1985. SETTING: The outpatient division of the Connecticut Mental Health Center in New Haven. SUBJECTS: Three hundred ninety-eight adult outpatients who had been maintained with neuroleptics for 3 months to 33 years at intake and who were free of persistent TD at intake with no history of persistent TD movements. OUTCOME MEASURE: New cases of persistent TD were defined as the presence of mild or more severe dyskinetic movements at two successive follow-up visits, using the Abnormal Involuntary Movement Scale. RESULTS: As of July 1, 1990, there were 62 new persistent cases of TD, yielding an average incidence rate of 0.053 per year and a 5-year risk of 20%. The TD rate was positively affected by age, being nonwhite, and neuroleptic dose, and it was inversely affected by years of previous exposure. Little or no effects were found for age at first neuroleptic exposure, type of neuroleptic, use of other psychiatric medications, and psychiatric diagnosis. CONCLUSIONS: For outpatients maintained for many years with neuroleptics, dose should be minimized to reduce the risk of TD. This strategy does not appear to be negated by prescribing frequent changes in dosage. Although the TD rate is greatest during the first 5 years of neuroleptic treatment, new persistent cases continue to occur many years after first exposure.

Noradrenergic function in schizophrenia.

Yohimbine, an alpha 2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 16 healthy subjects and 18 drug-free schizophrenic patients with (n = 10) and without (n = 8) tardive dyskinesia (TD). Outcome measures of this double-blind, placebo-controlled study included changes in behavior, plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) level, blood pressure, and heart rate. A subgroup of six patients experienced a notable dysphoric arousal reaction that occurred 60 to 90 minutes following administration of 20 mg of yohimbine, this reaction was not observed in healthy subjects. The schizophrenic group as a whole (not the subgroup) showed a statistical trend toward a greater yohimbine-induced increase in plasma MHPG level and systolic sitting blood pressure. The patients with TD did not differ from those without TD or from healthy controls in their response to yohimbine. These results do not support the hypothesis that noradrenergic dysfunction plays a strong central role in the pathogenesis of schizophrenia or TD. However, further studies of noradrenergic dysfunction in sub-groups of patients with schizophrenia are indicated.

Tardive dyskinesia. A discontinuation study.

Twenty-one nonschizophrenic and 12 schizophrenic outpatients with tardive dyskinesia (TD) were followed up for a mean of 12.0 and 8.6 months, respectively, following discontinuation of neuroleptic therapy. Of the 33 patients, only one demonstrated complete reversal of TD. Cumulative survival curves of the length of time to first improvement (reduction in movement ratings by 50% of baseline) did not differ between the two groups. The median time to first improvement was seven months. If a patient can be kept off of a neuroleptic regimen for 18 months, the estimated probability of showing a 50% reduction in movement is 87.2%. In the nonschizophrenic group, depressed mood was negatively correlated with severity of abnormal movements.

Intermittent vs maintenance medication in schizophrenia. Two-year results.

This is a 2-year, double-blind, placebo-controlled study of 101 patients, evaluating the relative efficacy of intermittent medication (given only when the patient shows early signs of relapse) compared with moderate doses of maintenance medication for stable schizophrenic outpatients. Patients were dropped from the study if they had three prodromal episodes in 1 year or if an episode lasted more than 9 weeks. Fourteen percent of patients given maintenance treatment were dropped from the study compared with 46% of intermittently treated patients. Relapse rates were 16% for patients given maintenance treatment and 30% for intermittently treated patients, a nonsignificant difference. Intermittently treated patients were receiving significantly less medication, but there were no differences found in drug side effects. There appears to be no advantage in using the intermittent approach, but we found that the use of an early intervention strategy reduced the relapse and rehospitalization rates for these patients.

N400 and semantic categorization in schizophrenia.

The N400 component of event-related potentials (ERPs) was investigated in medicated schizophrenic patients and normal controls in a semantic categorization task. The subjects' task was to indicate whether pairs of words were semantically related or unrelated. The ERPs to the unrelated second words of the pairs contained a negative component, N400, which was reduced and delayed in the patients. However, inspection of individual subjects' data indicated that N400 was abnormal only in a subgroup of schizophrenics. Abnormalities in the amplitude of N400 suggest impairments in semantic expectancies, whereas abnormalities in the latency of N400 suggest a delay in information processing.

Handedness and the risk of tardive dyskinesia.

Previous results from five cross-sectional studies are conflicting about the relationship between hand preference and tardive dyskinesia (TD): two report a greater TD prevalence in left handers, and three report a greater prevalence in right handers. To help resolve these inconsistencies, the handedness-TD association was assessed in the Yale TD Study, a large prospective cohort investigation of outpatients maintained with neuroleptics. A consistent monotonic association was observed between the handedness score and TD incidence (p = 0.009). The estimated rate ratio, comparing left and mixed handers with pure right handers, adjusted for confounders, was 0.25 (95% confidence interval = 0.09, 0.70). The handedness effect (higher TD rate in right handers) was stronger for subjects with fewer negative symptoms, and it was stronger for men than for women. Although the specific biological mechanisms are unclear, these findings may reflect cerebral laterality in the pathophysiology of psychiatric disorders, possibly in combination with asymmetrical action of neuroleptic exposure.

The effect of neuroleptic discontinuation on psychopathology, involuntary movements, and biochemical measures in patients with persistent tardive dyskinesia.

As some of the pharmacological activities of neuroleptic medication may involve pathophysiological mechanisms underlying schizophrenia and tardive dyskinesia (TD), it is useful to study patients undergoing medication discontinuation. In this study, 19 stable, neuroleptic-maintained patients with persistent TD underwent taper and discontinuation of their neuroleptic medication over a 3-week period, and multiple behavioral and biochemical (plasma HVA, MHPG, and prolactin) measures were obtained. The major finding was that early relapsing patients had lower baseline and a significantly greater increase in plasma HVA levels after discontinuation than nonrelapsing patients. In addition, patients exhibiting withdrawal-exacerbated TD had significantly lower plasma MHPG levels than patients not exhibiting this phenomenon. The clinical and pharmacological implications of these findings are discussed.

Tardive dyskinesia and plasma homovanillic acid.

Using 61 patients with tardive dyskinesia (TD) and 25 normal controls, we explored the possibility that plasma HVA may reflect alterations in central dopamine activity or clinical aspects of TD. There were no significant differences between the two groups in plasma HVA level. Analyses of variance with age and sex as independent variables revealed that the major variance in plasma HVA was accounted for by age in both TD patients (p less than 0.001) and normals (p less than 0.049). Examining the TD patients alone, using multiple regression analysis, revealed that age, neuroleptic dose, and severity of TD accounted for 40% of the variance in plasma HVA in males, with age alone accounting for 28%. By comparison, females showed no association to neuroleptic dose or severity, and age only accounted for 8.9%. When severity of TD was the criterion variable, neuroleptic dose, plasma HVA, and age accounted for 20% of the variance in severity in female TD patients and showed no relationship in males. Possible implications of these differing findings in male and female TD patients are discussed.

Dimensions of delusional experience.

The authors describe a scale designed to measure five dimensions of delusional experience: conviction, extension, bizarreness, disorganization, and pressure. Reliability was adequate to excellent on four of the dimensions, but only fair on the dimension of bizarreness. In 52 delusional patients, no two dimensions correlated highly with each other, indicating that the dimensions were not redundant. Factor analysis identified two factors from the five dimensions--delusional involvement and delusional construct. On the basis of these results the authors suggest that delusions are a multidimensional phenomenon; the results have implications for the measurement of delusions in clinical research and for the understanding of the structure of psychotic experience.

Serum prolactin and tardive dyskinesia.

The authors correlated the serum prolactin levels of 19 men with tardive dyskinesia, 29 postmenopausal women with tardive dyskinesia, and 21 men without tardive dyskinesia with the variables age, sex, antipsychotic dosage, and severity of illness. All subjects were taking antipsychotic medication. The prolactin levels of the 14 women with severe tardive dyskinesia were significantly higher than those of the 15 women with mild symptoms. The prolactin levels of the 8 men with severe tardive dyskinesia did not differ from those of the 11 men with mild symptoms. The authors discuss the sex-related association between prolactin and severity of tardive dyskinesia in the context of recent animal studies that have examined the effect of prolactin and estrogens on the striatum.

Serum dopamine beta hydroxylase activity and tardive dyskinesia.

A case-control study was done to test the effect of serum dopamine-beta-hydroxylase (DBH) activity on tardive dyskinesia (TD) among 85 schizophrenic outpatients treated with neuroleptics. In contrast to the results of several previous studies, we found no significant association between serum DBH activity and the occurrence or severity of TD, controlling for other TD predictors.

Estrogen replacement and tardive dyskinesia.

A double-blind randomized clinical trial was conducted among 10 post-menopausal women with tardive dyskinesia (TD) to test the effect of estrogen replacement of the severity of abnormal movements and other outcome variables. After 3 weeks of treatment, the mean Abnormal Involuntary Movement Scale (AIMS) score decreased by 38% in the estrogen group and by 9% in the placebo group; the difference between groups was marginally significant (p less than 0.10). However, the small sample size and the imbalance between groups in baseline AIMS scores do not allow us to rule out the confounding effects of other prognostic factors. There were no significant differences between treatment groups for parkinsonian and psychological symptoms at any visit or for changes in these variables between visits. The findings of this preliminary trial are consistent with the results of other human and animal investigations, and they support the need for future research to understand the role of estrogens in the neuropathology and treatment of TD.

The relationship of circulating estradiol to tardive dyskinesia in men and postmenopausal women.

In order to assess the relationship between tardive dyskinesia (TD) and baseline circulating concentrations of estradiol, prolactin and homovanillic acid, we studied 43 outpatient men and postmenopausal women on chronic antipsychotic medication. Serum estradiol did not correlate with severity of TD, antipsychotic medication dose, serum prolactin or plasma HVA. Multiple regression analysis indicated a significant relationship between plasma HVA and severity of TD in postmenopausal women. These findings support the hypothesis that estrogen might serve a protective role against neuroleptic-induced striatal dopamine pathology.

Review of incidence studies of tardive dyskinesia associated with typical antipsychotics.

Unless researchers make an organized effort, patients with tardive dyskinesia are difficult to study and easily lost to follow up. Because there is no treatment for tardive dyskinesia, investigators are obliged to study the natural history of the disorder and identify risk and prognostic factors to further understand pathophysiologic mechanisms and to guide prevention and treatment efforts. Abundant variability exists among incidence studies of tardive dyskinesia, depending to some extent on design issues. In this article, the design concepts of incidence and prevalence studies are described, along with results, methodological problems, and identified risk factors in various tardive dyskinesia incidence studies involving the use of typical antipsychotic medications.

Expected incidence of tardive dyskinesia associated with atypical antipsychotics.

Given the problematic nature of tardive dyskinesia in persons taking conventional antipsychotics, evaluation of newer atypical antipsychotic agents should include a systematic assessment of tardive dyskinesia liability. Results of a prospective double-blind, randomized study of schizophrenic patients who participated in 3 preclinical olanzapine studies and were treated with 5 to 20 mg/day of olanzapine (N = 1192) or haloperidol (N = 522) recently indicated a significantly lower risk of development of tardive dyskinesia with olanzapine treatment than haloperidol treatment. This article discusses the known effects of atypical antipsychotic medications on tardive dyskinesia movements (both withdrawal and persistent) and the incidence rate of tardive dyskinesia among schizophrenic patients undergoing long-term treatment with olanzapine or haloperidol.

Extrapyramidal side effects, tardive dyskinesia, and the concept of atypicality.

The most frequent problems associated with the older generation of antipsychotic agents are extrapyramidal side effects (EPS) and tardive dyskinesia. Neuroleptic-induced EPS are thought to be caused by blockade of nigrostriatal dopamine tracts resulting in a relative increase in cholinergic activity; tardive dyskinesia is less well understood but is thought to be a supersensitivity response to chronic dopamine blockade. The leading hypothesis for the mechanism of action of the newer generation of atypical antipsychotics is the presence of a high serotonin-to-dopamine receptor blockade ratio in the brain. When serotonergic activity is blocked-as is the case with atypical antipsychotics-dopamine release increases and balances out the dopamine blockade effect at postsynaptic receptor sites, which results in few or no EPS. Prospective data indicate that the risk of tardive dyskinesia in patients taking atypical antipsychotics is less than that for those taking typical antipsychotics. This article reviews the mechanisms of neuroleptic-induced EPS and tardive dyskinesia and discusses the relationship between these movement disorders and atypical antipsychotic agents.

Olanzapine and the new generation of antipsychotic agents: patterns of use.

As the new generation of atypical antipsychotics becomes available, the limitations of the older typical agents become apparent. The new medications, which have benefits other than the alleviation of positive symptoms of schizophrenia, may also be beneficial for psychotic disorders that have responded poorly to conventional neuroleptics. This article will describe the potential use of the atypical antipsychotics, especially olanzapine, for affective mood disturbances in schizophrenia, psychotic depression and mania, first-break schizophrenia, comorbid schizophrenia and substance abuse disorders, dementia in the elderly and those with late-onset schizophrenia, and behavioral problems in patients with mental retardation or developmental delays.

Formulary decisions and health economics.

Because of increasing concerns about health care costs, physicians must consider the cost-effectiveness of a treatment strategy, as well as its efficacy and safety. The question of whether the greater expense of a newer drug is justified over the cost of a generic drug deserves a comprehensive evaluation. The determination of effectiveness and tolerability of the newer antipsychotics should be expanded to include quality-of-life issues, reintegration of the patient into the community, resource utilization, and medical costs. There are clear indications that patients who take atypical antipsychotics utilize fewer medical resources than patients who take typical antipsychotics; however, the positive outcomes of the newer drugs must be translated into cost benefits if formularies are to be intelligently controlled.

Does loxapine have "atypical" properties? Clinical evidence.

Given findings at a pharmacologic level that loxapine has a ratio of serotonin (5-HT2) and dopamine (D2) binding affinity similar to that of the atypical antipsychotics, 1 review data at a clinical level to see if this agent has correlating effects on symptoms and behaviors. I conclude that there is reason to infer that loxapine may be more beneficial for negative symptoms and refractory states than other typical antipsychotic agents. However, because of the limitations within these older studies, controlled fixed-dose designs employing current outcome methodologies are needed before concluding that loxapine is an atypical antipsychotic agent.

Depot fluphenazine: risk/benefit ratio.

The risks and benefits associated with depot fluphenazine are reassessed by a review and critique of the literature, with an emphasis on controlled studies comparing depot to oral preparations. Specific gaps in our knowledge are noted and recommendations are made for future research.