Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.

BACKGROUND: Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months. METHODS: Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled. RESULTS: Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol. CONCLUSIONS: Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.

The statistical comparison of clinical trials.

Being able to compare clinical trials using statistically proven analyses is essential, but certain protocols must be followed if such a comparison is to be made. The difficulty of making meaningful statistical comparisons is illustrated in 5 clinical trials comparing atypical antipsychotics. Certain judgments can be made on the basis of internal and external validity, for example, but there are many other areas--effect size, for example--in which it is impossible to make any statistical comparisons across these trials because they were not conducted in a uniform fashion. In the final analysis, it is doubtful that the differences between atypical antipsychotics covered in these trials are greater than those due to chance.

Family treatment and medication dosage reduction in schizophrenia: effects on patient social functioning, family attitudes, and burden.

The effects of 2 family intervention programs (supportive family management [SFM], including monthly support groups for 2 years; or applied family management [AFM], including 1 year of behavioral family therapy plus support groups for 2 years), and 3 different neuroleptic dosage strategies (standard, low, targeted) on social functioning of patients with schizophrenia. their relatives' attitudes, and family burden were examined. AFM was associated with lower rejecting attitudes by relatives toward patients and less friction in the family perceived by patients. Patients in both AFM and SFM improved in social functioning but did not differ, whereas family burden was unchanged. Medication strategy had few effects, nor did it interact with family intervention. The addition of time-limited behavioral family therapy to monthly support groups improved family atmosphere, but did not influence patient social functioning or family burden.

Effects of behavioural family management on family communication and patient outcomes in schizophrenia.

BACKGROUND: Family interventions for schizophrenia have proved to be highly effective in preventing relapse, but it is not clear how they work or how they should be structured. AIMS: To examine the effects of a behavioural family intervention and a family support programme on communication, problem solving and outcome in order to determine the impact of structured communication training. METHOD: Patients and family members participating in the Treatment Strategies in Schizophrenia study were videotaped engaging in 10-minute problem-solving conversations at baseline and after the conclusion of the family intervention. Tapes were subsequently evaluated for changes in communication patterns. RESULTS: The intensive behavioural intervention did not produce differential improvement in communication, and change in communication was unrelated to patient outcomes. CONCLUSIONS: The data suggest that intensive behavioural family interventions may not be cost efficient, and that change in family communication patterns may only be important for a subset of families.

Evidence-based psychosocial treatment for schizophrenia.

Current recommendations for evidence-based schizophrenia treatment support a comprehensive, individualized approach that integrates advances in psychopharmacology with psychosocial strategies for disease management. In this issue of the Schizophrenia Bulletin, we invited clinician investigators to summarize new empirical data concerning the efficacy of psychosocial interventions that target common and particularly problematic aspects of schizophrenia. A rich formulary of psychosocial interventions with demonstrated efficacy is now available. With new neuroleptic medications, these interventions should define the current standard of care for schizophrenia.

Risperidone use at a state hospital: a clinical audit 2 years after the first wave of risperidone prescriptions.

BACKGROUND: In spite of some inherent limitations, naturalistic data can provide information on populations that have greater heterogeneity than can controlled clinical trials and on functional outcomes that may be especially important in clinical practice. In the present retrospective naturalistic study, we evaluated key clinical outcomes among the first wave of risperidone-treated patients at a state psychiatric hospital. METHOD: Outcome data were extracted from the charts of 142 patients 2 years after initiation of treatment with risperidone. Their diagnoses included DSM-III-R schizophrenia (57%), schizoaffective disorder (22%), dementia and other organic conditions (7%), bipolar disorder (5%), and other psychiatric disorders (9%). RESULTS: During the 2-year period, 92 of 142 patients were discharged from the hospital: 61 (43%) were discharged on risperidone treatment and 31 (22%) were discharged on treatment with other drugs. At the time of the study, 50 of 142 patients were still in the hospital: of these, 18 (13%) were still receiving risperidone. The modal maximum daily dose of risperidone was 4.1 mg in patients discharged on risperidone treatment and 7.5 mg in patients still in the hospital. All groups were granted more ward privileges after starting risperidone, the most being granted to patients discharged from the hospital on risperidone treatment (p<.05 versus patients discharged on treatment with other drugs) and those still receiving risperidone in the hospital. Significantly fewer patients discharged on risperidone treatment than on treatment with other drugs were readmitted to the hospital within 2 years after discharge (p<.01). CONCLUSION: Improved privilege levels and a reduced readmission rate indicate that risperidone was an effective antipsychotic agent among a heterogeneous patient population in a state hospital. These factors may be especially important to justify use of this agent in the current fiscal climate.

Landmark-based morphometric analysis of first-episode schizophrenia.

BACKGROUND: The goal of this investigation was to utilize landmark-based shape analysis and image averaging to determine the sites and extent of specific structural changes in first-episode schizophrenia. METHODS: Neuroanatomic structures identified on midsagittal magnetic resonance imaging (MRI) scans were compared between 20 patients with schizophrenia and 22 normal control subjects. The difference between averaged landmark configurations in the two groups was visualized as a shape deformation by a thin-plate spline and through averaged MRI images for both groups. RESULTS: A shape difference was found to be statistically significant; by inspection, it is contrast between differences in two closely abutting regions, involving primarily the posterior corpus callosum and upper brain stem--the "focus" is the relation between them. CONCLUSIONS: The findings are consistent with prior studies suggesting involvement in schizophrenia of the corpus callosum and the limbic structures contributing to the corpus callosum; the possibility of local pathology primarily involving the brain stem cannot be excluded. The methods of landmark-based shape analysis and image averaging utilized in this study can complement the "region-of-interest" method of investigating morphometric abnormalities by characterizing the spatial relationships among structural brain abnormalities in schizophrenia.

Eye tracking abnormalities in schizophrenia: evidence for dysfunction in the frontal eye fields.

BACKGROUND: Eye tracking deficits are robust abnormalities in schizophrenia, but the neurobiological disturbance underlying these deficits is not known. METHODS: To clarify the pathophysiology of eye tracking disturbances in schizophrenia, we tested 12 first-episode treatment-naive schizophrenic patients and 10 matched healthy individuals on foveofugal and foveopetal step-ramp pursuit tasks. RESULTS: On foveopetal tasks, the initiation of pursuit eye movements was delayed in schizophrenic patients, and their steady-state pursuit gain was reduced particularly at slower target speeds (8 and 16 deg/sec). In foveofugal step-ramp tasks, their primary catch-up saccades were normal in latency and accuracy, but their postsaccadic pursuit in the first 100 msec after the primary catch-up saccade was significantly reduced even relative to their slow steady-state pursuit, especially during and immediately after an acute episode of illness. CONCLUSIONS: These observations indicate that motion-sensitive areas in posterior temporal cortex provide sufficiently intact information about moving targets to guide accurate catch-up saccades, but that the sensory processing of motion information is not being used effectively for pursuit eye movements. Low-gain pursuit after the early stage of pursuit initiation suggests that the use of extraretinal signals about target motion (e.g., anticipatory prediction) only partially compensates for this deficit. The pattern of low-gain pursuit, impaired pursuit initiation, and intact processing of motion information for catch-up saccades but not pursuit eye movements, was consistent in the schizophrenic patients tested at five time points over a 2-year follow-up period, and implicates the frontal eye fields or their efferent or afferent pathways in the pathophysiology of eye tracking abnormalities in schizophrenia.

Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible?

Accumulating evidence suggests alterations in brain structure, especially in the prefrontal and temporal cortex, in schizophrenia. Previous studies examining the progression of brain structural alterations in schizophrenia have led to conflicting results. Morphometric studies of the superior temporal gyrus (STG) volumes were conducted in a series of neuroleptic-naive first-episode schizophrenic patients, non-schizophrenic first-episode psychotic patients, and matched healthy controls. Three-dimensional MRI scans were carried out in these subjects before and after one year of treatment. Volume reductions were seen at baseline in the left superior temporal gyrus (adjusted for intracranial volume) in both of the patient groups. Pretreatment illness duration was inversely related to the volume of the left superior temporal gyrus; this relation was confined to males. One-year follow-up MRI investigations in a smaller subset of patients suggested that the STG volume reductions may be reversible. No significant changes were noted in the STG volumes in matched healthy controls who were also scanned at baseline as well as at one-year follow-up. These findings have implications for understanding the nature of the neuropathological processes in early schizophrenia, as well as the potential impact of early treatment.

Clozapine withdrawal-emergent dystonias and dyskinesias: a case series.

BACKGROUND: Severe psychotic decompensation during clozapine withdrawal has been reported previously. Less attention has been paid to movement disorders following abrupt clozapine withdrawal. This report describes 4 subjects who experienced severe dystonias and dyskinesias upon abrupt clozapine withdrawal. METHOD: Current and past medical records of 4 subjects with DSM-IV schizophrenia or schizo-affective disorder were reviewed. RESULTS: All subjects had a history of neuroleptic-induced extrapyramidal symptoms, 1 had a history of severe dystonias, and 1 had neuroleptic malignant syndrome. All had mild orolingual tardive dyskinesia prior to clozapine treatment. All subjects had received clozapine for several months, and 3 of the 4 subjects stopped clozapine abruptly. Two subjects experienced cholinergic rebound symptoms within hours, which resolved quickly. These subjects had severe limb-axial and neck dystonias and dyskinesias 5 to 14 days after clozapine withdrawal. Two subjects were unable to ambulate, and 1 had a lurching gait. Two gagged while eating or drinking. Two subjects were returned to clozapine, 1 was started on low-dose risperidone treatment, and 1 was started on olanzapine treatment. All experienced significant improvements in their mental state and movement disorders. CONCLUSION: Severe movement disorders, which may be worse than the movements prior to clozapine treatment, and cholinergic rebound symptoms may occur upon abrupt clozapine withdrawal and must be recognized in addition to the severe psychotic decompensation noted in some patients. Patients, families, and caregivers must be alerted to this possibility. Where possible, a slow clozapine taper, the use of anticholinergic agents, and symptomatic treatment may help minimize these withdrawal symptoms, and reintroduction of clozapine or treatment with the newer atypical agents can help in the clinical management of these symptoms.

Research and treatment strategies in first-episode psychoses. The Pittsburgh experience.

BACKGROUND: Studies of first-episode patients allow investigation of the biological basis of psychotic disorders without the potential confounds of prior treatment and illness chronicity. Prospective studies of this population can clarify the impact of illness course and treatment on neurobiology. METHOD: We summarise preliminary findings from our ongoing magnetic resonance imaging and spectroscopy studies of first-episode schizophrenia patients being conducted prospectively from index evaluations through a period of two years; during this period, patients were treated with either a conventional antipsychotic such as haloperidol, or the atypical risperidone. RESULTS: Baseline neurobiological evaluations in first-episode schizophrenia patients have revealed evidence for structural and functional brain abnormalities consistent with a neurodevelopmental model of this illness. Our preliminary data support the value of risperidone as an antipsychotic drug of first choice among patients with early schizophrenic illness. CONCLUSIONS: Focused studies of first-episode patients have the potential to unravel pathophysiology of schizophrenic illness. Such knowledge is critical for more effective early detection, intervention and even prevention of this enigmatic disorder.

Hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria occurring early in clozapine treatment.

This report describes a 48-year-old caucasian male with schizophrenia who developed hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria early in clozapine treatment which resolved on drug discontinuation. The literature on similar cases is reviewed.

Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, Italy.

These guidelines for depot antipsychotic treatment in schizophrenia were developed during a two-day consensus conference held on July 29 and 30, 1995 in Siena, Italy. Depot antipsychotic medications were developed in the 1960s as an attempt to improve the long-term treatment of schizophrenia (and potentially other disorders benefiting from long-term antipsychotic medication). Depot drugs as distinguishable from shorter acting intramuscularly administered agents can provide a therapeutic concentration of at least a seven day duration in one parenteral dose. The prevention of relapse in schizophrenia remains an enormous public health challenge worldwide and improvements in this area can have tremendous impact on morbidity, mortality and quality of life, as well as direct and indirect health care costs. Though there has been debate as to what extent depot (long-acting injectable) antipsychotics are associated with significantly fewer relapses and rehospitalizations, in our view when all of the data from individual trials and metaanalyses are taken together, the findings are extremely compelling in favor of depot drugs. However in many countries throughout the world fewer than 20% of individuals with schizophrenia receive these medications. The major advantage of depot antipsychotics over oral medication is facilitation of compliance in medication taking. Non-compliance is very common among patients with schizophrenia and is a frequent cause of relapse. In terms of adverse effects, there are not convincing data that depot drugs are associated with a significantly higher incidence of adverse effects than oral drugs. Therefore in our opinion any patient for whom long-term antipsychotic treatment is indicated should be considered for depot drugs. In choosing which drug the clinician should consider previous experience, personal patient preference, patients history of response (both therapeutic and adverse effects) and pharmacokinetic properties. In conclusion the use of depot antipsychotics has important advantages in facilitating relapse prevention. Certainly pharmacotherapy must be combined with other treatment modalities as needed, but the consistent administration of the former is often what enables the latter.

The rationale and ethics of medication-free research in schizophrenia.

Schizophrenia research is receiving intense scrutiny from an ethical perspective. Medication-free protocols present a most vexing dilemma in that they greatly enhance the opportunity for advancing knowledge but also raise the prospect of withholding known effective treatment. In this article, we discuss the purpose of medication-free protocols in new drug development and nontreatment research. Potential benefits and risks associated with drug discontinuation are evaluated, and methods for minimizing risk and increasing benefits are proposed as guidelines for the protection of individual subjects. The complex problem of informed consent also is addressed. Medication-free research in schizophrenia is difficult, but it can be conducted relatively, safely with freely consenting, competent subjects. Assurance that studies meet this standard is required. We believe that such investigations can meet high standards of ethics and subject protection, and that a radical revision of procedures for research review and implementation is not indicated.

Relapse and rehospitalization during maintenance treatment of schizophrenia. The effects of dose reduction and family treatment.

BACKGROUND: Previous studies have examined dose reduction and family treatment in schizophrenia, but none has examined their interaction. This study assessed the impact of dose reduction of antipsychotic medication and family treatment on relapse and rehospitalization during maintenance treatment. METHODS: Subjects were 313 male and female outpatients at 5 centers with a DSM-III-R diagnosis of schizophrenia or schizoaffective disorder. In a 3 x 2 design, subjects were randomized to 1 of 3 medication strategies using fluphenazine decanoate under double-blind conditions: continuous moderate dose (standard) (12.5-50 mg every 2 weeks); continuous low dose (2.5-10 mg every 2 weeks); or targeted, early intervention (fluphenazine only when symptomatic). Subjects also were randomized to 1 of 2 family treatment strategies (supportive or applied). Supportive family management involved monthly group meetings. The more intensive applied family management involved monthly group meetings and home visits where communication and problem-solving skills were taught. Patients and families were treated and assessed for 2 years. RESULTS: Both continuous low-dose and targeted treatment increased use of rescue medication and relapse; only targeted treatment increased rehospitalization. This pattern was consistent across both family treatments; there were no differences between family treatments. CONCLUSIONS: These findings reaffirm the value of antipsychotic medication in preventing relapse and rehospitalization. The absence of family treatment differences may be because both conditions engaged families.

Adverse effects of risperidone on eye movement activity: a comparison of risperidone and haloperidol in antipsychotic-naive schizophrenic patients.

Risperidone is a novel and clinically effective atypical antipsychotic medication with a unique biochemical profile. To contrast the neurophysiological effects of this new medication with those of a typical antipsychotic medication, we performed quantitative measurements of saccadic eye movements in a series of antipsychotic-naive schizophrenic patients treated with either risperidone or haloperidol. Patients were tested before and after 1 month of treatment, and a matched group of healthy subjects was tested twice over a similar time interval. Risperidone, but not haloperidol, was associated with prolonged latency and decreased peak velocity and accuracy of saccadic eye movements that was detectable 4 weeks after treatment initiation. The adverse effects of risperidone may be due to the lack of development of acute tolerance to its powerful serotonergic (5-HT2A) antagonism, which could be responsible for the disruption of brainstem physiology in regions controlling saccadic eye movements.