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.

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.

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.

Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol.

BACKGROUND: Tardive dyskinesia is important in the side-effect profile of antipsychotic medication. AIMS: The development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years. METHODS: Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD), it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated. RESULTS: The relative risk of tardive dyskinesia for the overall follow up period for haloperidol (n = 522) v. olanzapine (n = 1192) was 2.66 (95% CI = 1.50-4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n = 513) and 7.45% with haloperidol (n = 114). The relative risk throughout this follow-up period was 11.37 (95% CI = 2.21-58.60). CONCLUSION: Our results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.

Neuroleptic-induced hyperprolactinemia.

Neuroleptic-induced hyperprolactinemia (NIHP) has been a 'cost' of traditional antipsychotic therapy. Because all of the traditional neuroleptics are capable of elevating serum prolactin, clinicians have had to accept the implications of NIHP along with the antipsychotic's efficacy. Accordingly, the clinical consequences of NIHP have received limited attention. With the introduction of some of the new, more highly selective mesolimbic and mesocortical dopamine-blocking, prolactin-sparing antipsychotic drugs, NIHP may now be prevented or minimized. Given this possibility, it becomes more important than ever that clinicians understand both the short- and long-term consequences of hyperprolactinemia and current management approaches.

Positive and negative symptoms and and adjustment in severely mentally ill outpatients.

Studying the relationships among clinical symptoms and adjustment can clarify prognostic factors in severe mental disorders, highlight syndromes that may be the focus of different treatments, and illuminate causal relationships connecting premorbid, 'acute', and long-term psychopathological features. This article examines the relationship between positive and negative symptoms and community adjustment in 398 community mental health center outpatients maintained on neuroleptic medication. Outcome measures include psychiatric hospitalization, employment, and social involvement. Affective symptomatology, premorbid social competence, and three neuropsychological measures are additional independent variables. Positive and negative symptoms are significantly correlated with separate aspects of contemporaneous adjustment, as well as with subsequent hospitalization. Negative symptoms are predominantly related to prior hospitalization, employment, and social interactions; positive symptoms are primarily related to subsequent hospitalization. Disordered attention is most related to global neuropsychological impairment; avolition is mainly associated with degree of employment. Findings are separable from the effects of schizophrenic vs. non-schizophrenic diagnosis. Special attention is paid to a central group of negative symptoms, to separating negative symptoms from neuropsychological deficits, and to distinguishing premorbid from current social functioning.

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.

Naltrexone augmentation of neuroleptics in schizophrenia.

This study was conducted to determine whether the addition of naltrexone to ongoing neuroleptic treatment would facilitate the reduction in positive or negative symptoms in patients with schizophrenia. Twenty-one patients meeting DSM-III criteria for schizophrenia were enrolled; all patients had been stabilized for at least 2 weeks on their dosage of neuroleptic medicine before entering the study. Patients were randomized to receive either placebo or naltrexone 200 mg/day for 3 weeks in addition to their neuroleptic. Patients randomized initially into the placebo arm were crossed over to receive naltrexone in a single-blind fashion for 3 additional weeks. All patients were rated weekly with the Brief Psychiatric Rating Scale (BPRS). Fifteen patients received placebo and six received naltrexone in the first 3 weeks. No significant effects of naltrexone on total BPRS scores or BPRS subscale scores were observed. Patients who received naltrexone on a single-blind basis at the end of the placebo-controlled trial demonstrated a transient exacerbation in negative symptoms as reflected by the total BPRS score and the BPRS Withdrawal-Retardation subscale score. Repeated-measures analysis of variance (ANOVA) on the BPRS total score of the subsequent treatment with naltrexone showed a trend for a significance in the drug by time effect. Repeated-measures ANOVA on the BPRS Withdrawal-Retardation subscale of the subsequent treatment with naltrexone showed a significant drug by time effect. The current data failed to indicate a clinical benefit when naltrexone was added to the neuroleptic regimen. Other potential applications of naltrexone in schizophrenia are addressed.

Clozapine reduces violence and persistent aggression in schizophrenia.

Violence and persistent aggression are serious problems in the general population and among certain psychiatric patients. Violence and persistent aggression have been associated with suicidal ideation and substance abuse, characteristics of chronically ill, and in many instances, treatment-resistant schizophrenia individuals. Assessment of dangerousness in psychiatric patients involves evaluation of sociodemographic and clinical factors. A substantial number of neurologic and psychiatric disorders are associated with pathologic anger and aggression; of these, the association between schizophrenia and violence/aggression is the best described. Neurotransmitters that have been implicated in aggressive and violent behavior include serotonin, norepinephrine, and dopamine. Current pharmacotherapy of pathologic aggression involves the use of multiple agents on a trial-and-error basis, with varying degrees of response. Unfortunately, this approach subjects patients to numerous side effects, including the extrapyramidal symptoms associated with the use of conventional antipsychotics. This paper will review evidence for the efficacy of clozapine in the treatment of aggression and violence in the treatment-refractory patient. The reduction in violence and persistent aggression with clozapine treatment should improve the chances for integration of the schizophrenia patient into the community and provide cost savings to society.