Margaret G. Woerner

Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder.

BACKGROUND Enhancing medication adherence early in the course of schizophrenia and schizoaffective disorder may substantially improve long-term course. Although extensively studied in multi-episode patients, little data exist on medication adherence by first-episode patients. METHOD Medication adherence was assessed during the first year of treatment and following recovery from the first relapse in patients treated by a standardized medication algorithm. RESULTS During the first year of treatment, patients with poorer premorbid cognitive functioning were more likely to stop antipsychotics (t=-2.54, df=75, p=0.01). Parkinsonian side effects increased the likelihood (hazard ratio=41.22; 95% CI=2.30, 737.89; p=0.01), and better executive function decreased the likelihood (hazard ratio=0.40; 95% CI=0.18, 0.88; p=0.02) that patients discontinued maintenance medication after a first relapse. CONCLUSION Interventions to ameliorate cognitive deficits and Parkinsonian side effects may enhance treatment adherence.

Tardive Dyskinesia: Prevalence, Incidence, and Risk Factors

Despite increased attention to the problem of tardive dyskinesia (TD), many questions remain unresolved. There is a consensus that neuroleptics play a substantial role in its development, but other variables must also contribute. Prevalence surveys have helped to define the scope of the problem and suggest risk factors for further study. Their usefulness has been limited by methodological problems including the difficulty of estimating false-negative (masked) dyskinesia and false-positive (movements caused by other neuromedical conditions) rates. A recent large scale survey reported an overall rate of abnormal involuntary movements of 23.4% among neuroleptic-treated psychiatric patients; the range was from 12.3% among outpatients at a Veterans Administration hospital to 37.4% among state hospital inpatients. Rates of covert dyskinesia, obtained by withdrawing medication from 70 TD negative cases, ranged from 17% for the Veterans Administration to 67% at the state hospital (overall rate, 34%). Very few clear false-positive cases were found. The incidence of TD, based on a large prospective study of young adult patients, is 19% after 4 years of cumulative neuroleptic exposure. Higher incidence rates have been found in prospective studies of older patient samples. Age remains the risk factor most consistently associated with TD development; it may also relate to increased persistence. Female sex among older populations, diagnosis of affective disorder, and evidence of neuroleptic-induced pseudoparkinsonism also relate to increased risk. Further work is needed to elucidate the role of dosage and length of neuroleptic treatment, as well as other potential contributory factors.

Psychobiologic correlates of treatment response in schizophrenia

In studies conducted on largely treatment naive patients in their first episode of psychosis, we have found that treatment outcome is quite good and that most patients recover or at least achieve a substantial degree of symptom remission. However, over the course of their illness and in the context of subsequent psychotic episodes, they may experience some decrease in their treatment response from illness progression. In addition, the heterogeneity of treatment outcome is associated with specific clinical (gender, primary negative symptoms of the deficit state, duration of psychosis) and biological variables (pHVA, ventricular volume). It is unclear whether these variables represent aspects of discrete subtypes of schizophrenia or dimensional measures of pathology within the broad context of a unitary disease entity.

Subject selection biases in clinical trials : Data from a multicenter schizophrenia treatment study

To evaluate subject selection biases in clinical trials, demographic characteristics (gender, race, and age) of subjects at different phases of evaluation for a multicenter maintenance trial in schizophrenia were examined. Six thousand twelve diagnostically appropriate subjects were screened for the study; of these, 1,320 met eligibility criteria and 528 (9% of the screened sample) entered the study. Women, blacks, and older subjects were more likely not to meet eligibility criteria; women and older subjects were more likely and blacks were less likely to refuse study participation. Overall, compared with the screened population, the sample of subjects who entered the study contained proportionately fewer women (33 vs. 43%), more blacks (48.5 vs. 41%), and fewer older subjects (mean age of the entered sample was 29.4 +/- 7.4 vs. 34.8 +/- 11.3 years for the screened population). Having identified these selection factors, a second goal was to assess the potential clinical relevance of selection biases of these magnitudes on clinical trials using models of hypothetical studies with different degrees of selection bias. These showed that selection biases would rarely change overall study outcomes to a clinically relevant degree. However, in our models, selection biases did limit the ability to make inferences about results for select small subgroups of the study population. Investigators should consider collecting data on the recruitment process to allow estimation of the effects of selection biases on the generalizability of their findings.

A Prospective Study of Tardive Dyskinesia Development: Preliminary Results

Preliminary findings from a prospective study of tardive dyskinesia (TD) development in a population of psychiatric patients suggest a TD incidence of 12% after 4 years of cumulative neuroleptic exposure. No cases of abnormal involuntary movements that might be mistaken for TD have been found in patients with no history of neuroleptic exposure. Early findings with regard to risk factors are discussed.

Methylphenidate response, psychopathology and tardive dyskinesia as predictors of relapse in schizophrenia

Despite the proven efficacy of acute and maintenance pharmacotherapy in schizophrenia, practical methods for identifying patients who require continuous treatment to prevent relapse have not been established. We hypothesized that a pathologic overactivity of mesolimbic and mesocortical dopamine neural systems, that mediates positive psychotic symptoms in the acute phase of the illness, persists in some outpatients who are vulnerable to relapse despite appearing clinically stable. To test and determine if putative measures of central nervous system dopamine activity predict outcome, 41 stable outpatients receiving neuroleptic maintenance treatment underwent provocative tests with methylphenidate in a randomized double-blind placebo controlled design in which behavioral, neuromotor, biochemical, and cardiovascular responses were measured. Patients were then withdrawn from medication and monitored for 52 weeks, or until relapse. The results indicate that psychotic symptoms and their activation by methylphenidate, and the presence of tardive dyskinesia are associated with each other and with a higher risk of relapse. These findings partially support our hypothesis and offer potentially useful measures for the identification of candidates for reduced dose neuroleptic maintenance treatment strategies in schizophrenia.

Cognitive impairment in tardive dyskinesia

Psychiatric patients in a prospective study on tardive dyskinesia (TD) development were psychometrically evaluated before TD onset to see whether cognitive impairment predisposes an individual to greater risk for TD. It was found that patients with TD showed more preexisting cognitive impairment than did the non-TD controls.

Obstetric complications in schizophrenia, schizoaffective disorder and normal comparison subjects

Previous studies have indicated that obstetric complications (OCs) may be risk factors for schizophrenia, but findings are inconsistent, and data about other diagnostic groups are relatively scarce. We compared the obstetric histories of subjects with schizophrenia, major affective disorder and normal controls. Our subjects included 61 schizophrenia, 26 schizoaffective, 28 major affective disorder patients and 21 normal controls. OCs were rated on the McNeil-Sjöström Scale using data from mothers reports and for a subsample from hospital and birth certificate records. The frequency of OCs did not differ statistically between diagnostic groups at any stage or for the three stages combined. OCs of at least level 4 were found in 69% of schizophrenia patients, 62% of schizoaffective patients, 68% of major affective disorder patients and 71% of the normal comparison group. OCs of at least level 5 were found in 23% of schizophrenia patients, 23% of schizoaffective patients, 21% of the major affective disorder patients and 14% of the normal comparison group. Our findings indicate that the etiologic significance of OCs may not be specific to schizophrenia.

Epidemiology of tardive dyskinesia.

Several major reviews have appeared in recent years discussing the epidemiology of tardive dyskinesia (TD) (1–3). Despite the increase in attention, many questions remain unanswered. It is hoped that epidemiological data will provide needed clues with regard to risk factors and etiology leading ultimately to successful preventive strategies. At present, the knowledge gained from epidemiological studies has not substantially improved our ability to prevent TD. This review will discuss some aspects of current knowledge and suggest possible strategies for future studies.As recent reviews (2,3) have pointed out, there have been serious methodological problems in most of the epidemiological studies of TD.

Side effects of antipsychotic drugs. Avoiding and minimizing their impact in elderly patients.

PREVIEW Clearly, the use of antipsychotic drugs can be extremely helpful in elderly patients to reduce psychotic symptoms and agitation. However, these drugs may produce serious side effects, such as parkinsonism, akathisia, dystonia, and tardive dyskinesia, that can range in intensity from mild to severe. In this article, the authors describe how to use antipsychotic agents in the most careful fashion possible.