Faculty Bibliography

High doses of antipsychotic medications are sometimes prescribed in clinical practice, although the efficacy and safety of such treatment have not been established. The purpose of this study was to determine whether high-dose, long-term antipsychotic treatment prescribed on the basis of clinical judgment can be justified. Patients who were receiving high doses of haloperidol were screened, and those patients whose plasma levels were at least 15 ng/mL were randomly assigned to an experimental group (N = 11) or to a control group (N = 12). The experimental group underwent a dose reduction to achieve the target plasma level of 10 ng/mL. The reduction was gradual over a period of 12 weeks. The control group treatment was maintained at the original level. Both groups were then followed up for another 16 weeks, during which the plasma levels of haloperidol were kept constant. The study used double-blind procedures. Both groups showed an average slight symptom reduction. There was no significant difference in the severity of symptoms between the two groups at any time point. The dose reduction had no apparent adverse effects. Thus, the results of this study did not provide justification for high-dose, long-term antipsychotic treatment. However, these results must be interpreted with caution because the sample studied here was small and biased

BACKGROUND: Valproate was initially introduced as an antiepileptic agent in 1967, but has been used over the years to treat a variety of psychiatric disorders. Its use in the treatment of patients exhibiting aggressive and violent behaviors has been reported in the literature as far back as 1988. However, these reports are uncontrolled, which is in marked contrast to the actual wide and established use of valproate for the treatment of aggressive behaviors. The aim of this report is to critically review the available data on valproate's use in nonbipolar patients with aggressive and violent behaviors. DATA SOURCES: The MEDLINE and PsycLIT databases were searched for all reports published from 1987-1998 containing the keywords valproate, the names of all commercial preparations, aggression, and violence. STUDY FINDINGS: Seventeen reports with a total of 164 patients were located. Ten of these were case reports with a total of 31 patients. Three were retrospective chart reviews with 83 patients, and 3 were open-label prospective studies with a total of 34 patients. No double-blind, placebo-controlled study could be found. An overall response rate of 77.1% was calculated when response was defined as a 50% reduction of target behavior. Most frequent diagnoses recorded were dementia, organic brain syndromes, and mental retardation. The antiaggressive response usually occurred in conjunction with other psychotropic medication. The dose and plasma valproate level required for response appeared to be the same as in the treatment of seizure disorders. DISCUSSION: While valproate's general antiaggressive effect is promising, in the absence of controlled data, conclusions are limited at this time. Specific recommendations for study design are given to obtain interpretable data for this indication

Agitation is a nonspecific constellation of relatively unrelated behaviors that can be seen in a number of different clinical conditions, usually presenting a fluctuating course. Multiple underlying pathophysiologic abnormalities are mediated by dysregulations of dopaminergic, serotonergic, noradrenergic, and GABAergic systems. Pathophysiologic mechanisms of agitation that operate in the different clinical disorders where agitation occurs are discussed. These pathophysiologic abnormalities are not associated with distinct clinical features. Although there may be a final common pathway, there is no unifying etiologic pathophysiology. The author suggests that the clinician address the underlying pathophysiology through a treatment intervention that addresses the overarching psychiatric disorder. Generally, agents that reduce dopaminergic or noradrenergic tone or increase serotonergic or GABAergic tone will attenuate agitation, often irrespective of etiology

Treatment resistance constitutes a significant dilemma in schizophrenia since it affects a substantial number of patients, their families and the health care professionals involved in their care. Nonresponsiveness needs to be approached as a multidimensional syndrome by specifying which symptoms in the spectrum of positive symptoms, negative symptoms, excitement/hostility, cognitive symptoms, and anxiety/depression are failing to respond to treatment. This review presents some of the clinical, demographic and biological correlates of nonresponse, in addition to compliance issues, psychosocial factors or side effects and as-yet-untreated comorbidities as a source for nonresponse. The effects of the atypicals clozapine, olanzapine, risperidone and quetiapine as compared to typicals are reviewed using available double-blind studies in this treatment refractory group of schizophrenia patients. The limited number of reports on the comparison of atypical compounds amongst each other are critically presented. Given that a subset of patients still do not respond to these agents, clinicians are using various augmentation strategies. We review studies with augmentation strategies which remain difficult to interpret given the open label and uncontrolled nature of most of these studies

BACKGROUND: Few controlled studies have compared the efficacy of clozapine and risperidone in treatment-refractory schizophrenic patients. The present study investigates the efficacy of both clozapine and risperidone on psychopathologic and neurocognitive measures in a prospective 12-week open-label trial in treatment-refractory schizophrenic patients from state psychiatric hospitals. METHOD: Thirty-five DSM-IV schizophrenic patients with a documented history of nonresponse to typical neuroleptics were treated with either clozapine or risperidone. Response was assessed every 2 weeks by independent raters with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scale, neurologic rating scales, and plasma drug levels. Neurocognitive tests were administered at baseline and week 12. RESULTS: Both clozapine and risperidone brought about significant (p < .003) overall improvement in psychopathology. However, clozapine was numerically superior to risperidone on PANSS total scores and PANSS positive, negative, excitement, and cognitive factors. Extrapyramidal side effects were minimal for clozapine, whereas some were present for risperidone. Patients taking risperidone improved significantly in the beginning stages of the study and remained stable thereafter. Patients taking clozapine showed a gradual improvement that occurred over the entire length of the trial. Neurocognitive measures showed minimal improvement and did not differentiate between the 2 medication groups. CONCLUSION: Both clozapine and risperidone were comparably effective across a wide spectrum of psychopathologic measures. While the efficacy of clozapine was only numerically superior to that of risperidone, it was associated with fewer extrapyramidal side effects and with progressive improvement over the 12-week treatment period, suggesting that in longer trials clozapine may prove to be superior to risperidone in neuroleptic-refractory patients

OBJECTIVE: The CNS metabolic response to a neuroleptic challenge in treatment-responsive and nonresponsive schizophrenic patients was measured in order to examine the relation between treatment outcome and the capacity to alter neurochemical function in response to acute receptor blockade. METHOD: Positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) were used to measure regional cerebral metabolism in seven schizophrenic patients judged to have been responsive to drug treatment previously and seven nonresponsive schizophrenic patients after a drug-free period of at least 3 weeks (baseline) and again 12 hours after administration of 5.0 mg of haloperidol. RESULTS: The haloperidol challenge caused widespread decreases in absolute metabolism in the nonresponsive patients but not the responsive patients. These group differences reflect the findings on the second (challenge) scans, since metabolic values at baseline were not statistically different in the two groups. The pattern of decreased metabolic activity in the nonresponders after the haloperidol challenge is similar to that previously observed in normal subjects. CONCLUSIONS: The metabolic response to drug challenge separates treatment responders from nonresponders and normal subjects. The results suggest that subtyping of schizophrenia (and other psychiatric disorders) can be achieved by measuring the physiologic response to a pharmacologic challenge in vivo with chemical brain-imaging techniques