The role of parkinsonism and antiparkinsonian therapy in the subsequent development of tardive dyskinesia

Tardive dyskinesia (TD) is a side effect of prolonged neuroleptic treatment presenting as abnormal involuntary movements. This troublesome disorder occurs in only 15-30% of patients taking neuroleptics, suggesting that these individuals may be physiologically distinct so as to be predisposed. This study analyzed possible factors contributing to TD development. Fifty patients on depot neuroleptics for more than 7.1 years were prospectively examined for TD and drug-induced parkinsonism (DIP) using the Smith-Trims rating scale for an average of 5 years. The patients were assessed for the severity of the movement and if the movement increased or decreased with respect to neuroleptic dosage, anticholinergic dosage, parkinsonism, and other related factors. Both TD and DIP increased over time. In the patients whose dose of neuroleptic decreased, the increase in TD ratings was not significant. Using a forward stepwise regression DIP was found to increase as TD worsened but did not appear to predict subsequent TD development. Anticholinergic treatment showed a less significant correlation with the change in TD. These results have implications for the management of combined TD and DIP presentation.     

Neuropsychological impairment in Tardive dyskinesia.

Tardive dyskinesia (TD) is a movement disorder secondary to neuroleptic treatment. Whether TD is associated with neurocognitive dysfunction is a controversial issue. We reviewed 31 published studies evaluating neuropsychological (NP) test results in schizophrenic patients with and without TD and found that TD was generally reported to be associated with cognitive impairment. Numerous methodological limitations, however, restrict the conclusions made about the relationship between cognition and dyskinesia. We therefore undertook a study in which 143 schizophrenic patients were evaluated on a comprehensive NP test battery. On both global and learning deficit scores, TD patients demonstrated greater impairment than did a matched comparison group. Two aspects of TD (severity and topography) were related to severity of cognitive impairment. These findings suggest that dyskinesia and cognition may share some underlying mechanism in schizophrenia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Current topics in tardive dyskinesia in Japan

This article reviews current topics in tardive dyskinesia (TD), a movement disorder associated with the prolonged use of neuroleptic agents, especially therapeutic and preventive strategies which have been or are now being studied in Japan. Tardive dyskinesia has become a major problem in the clinical psychiatric field since the early 1970s in Japan, lagging behind Western countries by more than 10 years. The average prevalence rate of TD has been estimated as 7.7% in Japan, while it has been reported in the English literature at around 15 to 20%. Clinical trials of treatments for TD have been or are now being performed in Japan with a number of novel compounds, such as ceruletide, meclofenoxate, and rolipram; however, no effective treatment has yet been established and measures to prevent TD have therefore been emphasized. These include (i) the development of new antipsychotic drugs which are free from TD, (ii) the identification of risk factors from prospective longitudinal studies, and (iii) the investigation of genetic variations that could act as a marker to identify especially vulnerable patients within the whole population of patients who need neuroleptic therapy.     

Blood biogenic amines during clozapine treatment of early-onset schizophrenia

The aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14-22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 +/- 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11-20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n = 7) and nonresponders (n = 8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therapeutic actions of the atypical neuroleptic clozapine.     

Do atypical antipsychotic medications favorably alter the long-term course of schizophrenia?

Schizophrenia is characterized by the greatest degree of clinical deterioration in the first decade following onset of psychosis; in fact, deterioration begins even prior to the onset of frank psychotic symptomatology. While somewhat controversial, it appears that effective early antipsychotic treatment might limit the extent of such deterioration. The newer, atypical antipsychotics such as clozapine, risperidone, olanzapine and quetiapine appear to have antipsychotic efficacy at least equal to the traditional neuroleptics, but with a much more favorable side effect profile. Clozapine is also effective in treating neuroleptic-refractory schizophrenic patients. Data suggest that in comparison to conventional agents, treatment with atypical antipsychotics may be associated with a more benign course of schizophrenic illness. Whether these atypical antipsychotics are associated with greater efficacy in limiting clinical deterioration in schizophrenic illness than traditional neuroleptics is, however, unclear. The following questions will be addressed in this paper: (i) Do atypical antipsychotics differ from traditional neuroleptics in modifying the natural course of symptomatology in schizophrenic illness? (ii) Do atypical antipsychotics differ from typical neuroleptics in modifying the natural course of neurobiological and cognitive abnormalities in schizophrenic illness? (iii) Do atypical antipsychotics differ from typical neuroleptics in modifying the natural course of psychosocial dysfunction in schizophrenic illness? (iv) Are there differences between typical and atypical antipsychotics with regard to their effects on the cost of care and resource utilization? The implications of the answers to these questions for the long-term treatment of schizophrenia will be discussed.     

Intermittent neuroleptic treatment and risk for tardive dyskinesia: Cura?ao Extrapyramidal Syndromes Study III

OBJECTIVE: The authors examined the association between three lifetime medication variables (cumulative amount of neuroleptics, number of interruptions in neuroleptic treatment, cumulative amount of anticholinergics) and the occurrence and severity of tardive dyskinesia. METHOD: The study was conducted in the only psychiatric hospital of a well-defined catchment area (the Netherlands Antilles). For all patients who had a history of taking neuroleptics for at least 3 months and were currently using neuroleptics (N = 133, mean age = 51.5 years), the presence and severity of tardive dyskinesia were measured with the Abnormal Involuntary Movement Scale. RESULTS: Of the three lifetime medication variables, only the number of neuroleptic interruptions was significantly related to tardive dyskinesia. The risk of tardive dyskinesia was three times as great for patients with more than two neuroleptic interruptions as for patients with two or fewer interruptions. CONCLUSIONS: This finding supports the schizophrenia protocol of long-term neuroleptic treatment rather than targeted or intermittent neuroleptic treatment.     

Phase-IV multicentre clinical study of risperidone in the treatment of outpatients with schizophrenia. The RIS-CAN-3 Study Group

OBJECTIVE: Since most clinical trials of atypical antipsychotics have been conducted in hospitalized patients, a Phase-IV, multicentre, 8-week, open-label, flexible-dose study was performed to assess the efficacy and safety of risperidone in outpatients with schizophrenia. METHOD: Three hundred and thirty patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) diagnosis of schizophrenia were enrolled at 61 Canadian sites. Upon trial entry, the patients had their neuroleptic and antiparkinsonian drugs discontinued, and treatment with risperidone was initiated at a dose of 2 mg daily, then increased by 2 mg daily on each of the 2 following days until the initial target dose of 6 mg daily was reached on day 3. No further titration was allowed until day 14, after which the dose could be increased or decreased. RESULTS: During the stabilization phase (days 14-56), the dose was unchanged in 44% of the patients, increased in 24%, decreased in 23%, and titrated both up and down in 9% of the patients. In the efficacy-evaluable population (n = 292), treatment with risperidone produced substantial (-26.4) and significant (P = 0.0001) improvement in the total Positive and Negative Syndrome Scale (PANSS) score. At the end of the study (week 8), 85% of patients were classified as clinically improved according to an a priori definition (that is, 20% or more decrease from baseline in total PANSS score). On their last study visit, 75% of patients reported their experience with risperidone as better than their previous neuroleptic therapy. Risperidone was generally well tolerated. The adverse events reported by more than 5% of the patients were insomnia, nausea, headache, somnolence, dizziness, fatigue, anxiety, vomiting, and ejaculation disorder. Seventy-four percent of the reported treatment-related adverse events were recorded during the first 2 weeks of the trial, possibly because of the discontinuation of prior neuroleptic and antiparkinsonian drugs followed by immediate upward titration of risperidone. However, only 8.5% of adverse events were reported to have occurred during week 3, and only 0.8% of adverse events were reported for week 8. Risperidone treatment produced significant improvements over baseline in the incidence and severity of extrapyramidal symptoms (EPS). A slight but statistically significant increase in body weight was observed. CONCLUSIONS: The results of this open-label, Phase-IV trial in a large population of outpatients with schizophrenia found that risperidone was superior to the neuroleptics that patients had previously taken in terms of efficacy and severity of EPS. Our results suggest the use of risperidone at lower doses in outpatients with schizophrenia.     

Relation of neuroleptic and anticholinergic medication to cognitive functions in schizophrenia.

In this article, we review research designed to examine the influence of neuroleptic and anticholinergic drugs on cognitive processes in schizophrenia. The review is motivated by the recognition that pharmacotherapy is an important factor in psychological research in schizophrenia, given that the great majority of patients studied in investigations of cognition receive both of these drugs. We find that neuroleptic treatment is associated with limited normalization on many psychological measures, whereas anticholinergics appear to disrupt some aspects of memory. Subject selection criteria, research designs, and drug measurement methods important in the evaluation of possible drug effects in psychological studies are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glucose and galactose transport in Bifidobacterium bifidum DSM 20082

The onset of psychosis during pregnancy presents several difficult management decisions and a careful risk-benefit analysis is required. Withholding antipsychotic treatment may produce more risks than benefits. Studies on neuroleptic teratogenicity are contradictory. Most of the commonly used neuroleptics exhibit a pregnancy risk of category C. Neuroleptic use during pregnancy may be associated with adverse effects in the pre- and postnatal period. These concerns include compromising uterine blood flow, post-partum neonatal sedation, and extrapyramidal signs expressed in the neonate. Each neuroleptic exhibits a unique pharmacokinetic profile. The antipsychotic properties and side effects considered most significant include sedation, half-life, hypotension, and apparent hydrophilicity. In this case study a decision to select molindone was based on these parameters.     

Tumour of the pancreas with unusual clinicopathological features

Antihistamines are frequently administered to psychiatric patients for a variety of purposes. Several large studies of schizophrenics have revealed an extremely high prevalence of Alzheimer's disease neuropathology compared with that in the general population. The neuroleptic treatment of schizophrenia appears to be implicated in this phenomenon. Many of the neuroleptics have anticholinergic effects, some being antihistamines as well, including chlorpromazine. It is proposed here that anticholinergics, including many antihistamines, either exacerbate the Alzheimer process or possibly contribute to its etiology/pathogenesis through their effects on cerebral cholinergic systems. Parsimony in the use of antihistamines thus appears to be warranted both for non-patients and schizophrenics pending the resolution of this issue.     

Low superoxide dismutase activity in schizophrenic patients with tardive dyskinesia

BACKGROUND: Tardive dyskinesia (TD) is a therapy-resistant adverse effect of neuroleptics. Although the exact pathophysiology of TD is unknown, oxygen radicals have been speculated to play a role in TD based on several lines of evidence. Superoxide dismutase (SOD) is a key enzyme which scavenges oxygen radicals. The authors investigated the association between erythrocyte SOD activity and TD. METHODS: Erythrocyte SOD activities were measured, blinded as to the presence or absence of TD. In 30 patients with schizophrenia who had been on typical neuroleptics for more than 10 years. TD severity was independently assessed, using the abnormal involuntary movement scale (AIMS), by two raters. RESULTS: There was a significant decrease in erythrocyte SOD activity in the definite TD group (N = 10) as compared with the no TD (N = 8) and questionable TD (N = 12) groups. Erythrocyte Cu,Zn-SOD activities correlated with AIMS scores. CONCLUSIONS: Patients with TD had low SOD activities as compared to those without TD. As a causal link between SOD activity and TD was not established in this study, larger prospective studies are warranted to determine whether patients with low SOD activity are susceptible to neuroleptic-induced TD.     

Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia

OBJECTIVE: This study examined whether subcortical volumes of the basal ganglia and thalamus in schizophrenic patients are related to neuroleptic exposure and symptom severity. METHOD: Basal ganglia substructures and thalamic volumes were measured with magnetic resonance imaging in 96 patients with schizophrenia (50 men and 46 women) and 128 healthy comparison subjects (60 men and 68 women). Twenty-one of the patients were neuroleptic-naive; of the 75 previously treated patients, 48 had received typical neuroleptics only, and 27 had received typical and atypical neuroleptics. The relation of volume measures to treatment status, exposure to neuroleptics, and symptoms was examined. RESULTS: The neuroleptic-naive patients did not differ from the healthy comparison subjects in subcortical volumes except for lower thalamic volume. In the neuroleptic-naive group, volumes did not correlate with severity of negative symptoms, but higher volumes in both the thalamus and the putamen were associated with more severe positive symptoms. The previously treated group showed higher volumes in the putamen and globus pallidus than the healthy comparison subjects and the neuroleptic-naive patients. In the treated group, a higher dose of a typical neuroleptic was associated with higher caudate, putamen, and thalamus volumes, whereas a higher dose of an atypical neuroleptic was associated only with higher thalamic volume. Higher subcortical volumes were mildly associated with greater severity of both negative and positive symptoms. CONCLUSIONS: Increased subcortical volumes in treated schizophrenic patients seem to be medication-induced hypertrophy. This hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment.     

Association of plasma homovanillic acid with behavioral symptoms in patients diagnosed with dementia: a preliminary report

Neuroleptic treatment of psychotic symptoms or agitated behavior in elderly patients diagnosed with dementia is associated with reduced efficacy and increased rates of neuroleptic-induced parkinsonism in comparison to younger patients with schizophrenia. We report the first study to examine the relationship between an in vivo measure of dopaminergic function, plasma homovanillic acid (pHVA), and ratings of psychosis, agitation, and parkinsonism before and after neuroleptic treatment in dementia patients. Pretreatment pHVA was significantly correlated with parkinsonian rigidity, with a trend observed with agitation and hostility. Though mean pHVA did not change during perphenazine treatment, intraindividual change in pHVA at day 15 was correlated with improvement in hostility, with a similar trend for improvement in agitation. These preliminary findings are consistent with reports associating dopaminergic function with agitated, but not psychotic, symptoms in patients diagnosed with dementia, and with a reduced responsivity of dopaminergic systems to neuroleptic treatment in these patients.     

Psychotic exacerbations produced by neuroleptics

Thirteen schizophrenic patients who developed abnormal psychotic behavior as an adverse reaction to a neuroleptic are described. A. Three patients showed a marked increase in the psychopathology during neuroleptic treatment. These episodes were treated by decreasing or discontinuing the neuroleptics. They did not respond to anticholinergic durgs nor did they respond to an increase in dosage, (another side effect previously reported and referred to here) indeed this treatment worsened the situation. B. Ten patients showed a mixed picture of catatonic excitement or inhibition on neuroleptics and several developed hallucinatory episodes. All of these exacerbations were terminated by anticholinergic injections. Other more familiar CNS abnormalities produced by neuroleptics are briefly discussed.     

Olanzapine: a serotonin-dopamine-receptor antagonist for antipsychotic therapy

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage and administration, and cost of olanzapine are reviewed. Olanzapine is a serotonin-dopamine-receptor antagonist indicated for use in the treatment of schizophrenia and other psychotic disorders. The affinity of olanzapine for neuroreceptors is similar to that of clozapine. The drug is well absorbed from the GI tract; food has no effect. Olanzapine is more effective than placebo and equal to haloperidol in reducing psychotic symptoms on two rating scales. However, unlike typical dopamine-receptor antagonists used for antipsychotic therapy, olanzapine is more effective in reducing the negative symptoms of schizophrenia. The most frequent adverse drug reactions (ADRs) associated with olanzapine are somnolence, agitation, insomnia, and headache. Constipation and dry mouth occur as dose-dependent ADRs. Unlike clozapine, olanzapine does not cause agranulocytosis. No cases of tardive dyskinesia or neuroleptic malignant syndrome have been reported. Olanzapine has been associated with slight increases in hepatic transaminases. More study is needed to determine whether olanzapine interacts significantly with other drugs. The recommended starting dosage is 5-10 mg orally once daily. Efficacy beyond six weeks has not been evaluated; patients treated for longer than six weeks should be periodically reassessed. Olanzapine costs about 10 times more than typical antipsychotics because a generic version is not available; however, olanzapine costs less than clozapine therapy and may cost less than haloperidol in terms of total health care costs. Olanzapine offers an effective alternative for treating schizophrenia and has a favorable adverse-effect profile.     

GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats

Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if TD may be a result of neuroleptic-induced excessive stimulation of striatal glutamate receptors, the effect of the anti-excitotoxic GM1 ganglioside was studied in a rat model of TD. In an acute experiment each of four groups of rats was treated with GM1 20 mg/kg SC+saline IP, saline SC+haloperidol 1.2 mg/kg IP, GM1 SC+haloperidol IP, or saline SC+saline IP. In a subsequent long-term experiment lasting 16 weeks, each of the four groups was treated as in the acute experiment, with the exception that haloperidol was injected IM as decanoate 38 mg/kg every 4 weeks, and the controls received vehicle injections. The behavior was videotaped and scored at intervals during both experiments, including 16 weeks after cessation of the long-term treatment. Haloperidol induced a significant increase in vacuous chewing movements (VCM) and immobility both in the acute and in the long-term experiment. Other categories of behaviour (rearing, moving, sitting) were significantly affected only in the acute experiment. GM1 did not affect any of the acute behavioural effects of haloperidol, but significantly reduced VCM in the long-term experiment. The effects on VCM of haloperidol and GM1 persisted for at least 8 weeks after cessation of the long-term treatment. These results suggest that long-lasting changes in striatal function induced by excessive glutamate receptor stimulation may be a mechanism for the development of VCM in rats and perhaps also for TD in humans.     

The meaning and management of neuroleptic medication: a study of patients with a diagnosis of schizophrenia

The meaning of medication and the way in which people use medicines has been the focus of a number of studies in recent years. However, there has been little attention directed to the meaning and management of neuroleptic medication by people who have received a diagnosis of schizophrenia. This topic is highly relevant to policy because of the central role given to neuroleptics in contemporary mental health and community care services. Using data from in-depth interviews with people with a diagnosis of schizophrenia we explore patients reasons for taking neuroleptics and the ways in which patients self-regulate their medication. The data suggest that the main utility of taking neuroleptic medication is to control specific symptoms and to gain personal control over managing symptoms. The costs of taking medication were side-effects which at times equalised or outweighed the positive gains of the neuroleptic medication. Patient accounts suggest that everyday medication practices are to a significant degree related to a policy context which stresses the need to survey and control the behaviour of people living in the community and the wider meaning and symbolic significance that schizophrenia has for patients in their everyday lives. For this reason, self regulatory action in this group of patients tends to be less evident and the threat of external social control greater than patients taking medication for other chronic conditions. The findings suggest the need to develop a collaborative patient-centred model of medication management for patients diagnosed with schizophrenia.     

Immunohistochemistry diagnosis of fungal infections

BACKGROUND: A potential beneficial outcome of treatment with certain of the atypical neuroleptics is the reduced risk of cognitive impairment, stemming from purported low affinity for cholinergic receptors. In vitro experiments have shown that clozapine is highly anticholinergic and risperidone is minimally so. In vivo tests of the anticholinergic burden imposed by these medications and its potential cognitive consequences are needed. This study examines anticholinergic burden in schizophrenia patients taking clozapine and risperidone and tests whether this burden is associated with cognitive deficits. METHOD: Serum anticholinergic levels were determined in a sample of 22 chronic schizophrenia patients using the radioreceptor assay method of Tune and Coyle (1980). Fifteen patients received clozapine; 7 received risperidone. Mean +/- SD age of the sample, comprising 12 men and 10 women (68% white), was 44.7 +/- 8.4 years. Mean +/- SD age at onset of schizophrenia illness was 23.5 +/- 7.4 years. Two anticholinergic assays based on blood samples collected 1 week apart were available on each patient. RESULTS: Data indicated that clozapine patients had significantly (p < .001) higher anticholinergic levels at both collection points, and levels for both drugs remained stable over time. The clozapine and risperidone patients had essentially equivalent scores on the cognitive measure. CONCLUSION: These data suggest that anticholinergicity distinguishes clozapine and risperidone in vivo but that this effect is not associated with differences in global cognitive functioning. Results suggest that clozapine, despite producing moderately high in vivo serum anticholinergic levels, still holds clinical advantage over standard neuroleptics in terms of cognitive side effects. Reasons for this lowered risk of cognitive impairment are discussed.     

Intensive hospital monitoring of adverse reactions to benzodiazepines and neuroleptic agents

BACKGROUND: The main aims of the programme were to highlight the incidence of adverse reactions to the drugs monitored and to define the risk/benefit ratio taking account of the main physiological and physiopathological variations of patients. This paper reports the results of the programme regarding to adverse effects correlated to the use of some psychiatric drugs (benzodiazepines and neuroleptics). METHODS: A total of 73 records were compiled for 64 patients treated with benzodiazepines and/or neuroleptics. RESULTS: A very high mean incidence of adverse events was documented (48%) without any severe undesirable effects. 92% of patients treated with neuroleptics reported adverse events. Haloperidol, which caused adverse effects in 80% of patients, revealed mild or moderate forms of parkinsonism (15%), spasm (15%), rigidity (10%), akathisia (5%), reversible postural hypotension (10%), temporary reduction of the visual field (10%), delayed menstrual flow (5%), xerostomia (10%), excessive sweating (10%) and sialorrhea (10%). All the patients treated with clozapine showed adverse effects including postural hypotension (29%), persistent tachycardia (14%), sialorrhea (29%), excessive sweating (14%) and akathisia (14%). Spasms (25%), rigidity (25%) and akathisia (25%) were correlated to the use of clothiapine, whereas postural hypotension was referred to clopenthixol. 44% of patients treated with benzodiazepines showed undesired effects. 20% of those taking chlordemethyldiazepam showed somnolence (33%), sedation (22%) and dysar-thria (44%). Prolonged sedation was observed in 30% of all patients treated with lorazepam. Prazepam was correlated with adverse effects in 75% of cases. No adverse event was documented with bromazepam. CONCLUSIONS: A higher incidence of adverse events was documented than literature data. Further periods of intensive monitoring will be required to obtain a greater quantity of data from the intensive monitoring of adverse events through the MIO '97 programme.     

Pharmacotherapy of first-episode schizophrenia

BACKGROUND: A growing interest in first-episode schizophrenia reflects the belief that this line of investigation will lead to further developments regarding schizophrenia's aetiology, course and outcome. METHOD: Evidence from more recent clinical trials involving first-episode schizophrenia is integrated with neuroimaging data, specifically positron emission tomography, to provide direction regarding pharmacotherapy. RESULTS: Individuals with a first episode of schizophrenia appear particularly responsive to pharmacotherapy, as well as quite sensitive to side-effects. At the same time, current clinical and receptor-binding data support the efficacy of low-dose neuroleptic treatment. CONCLUSIONS: Early and effective treatment of schizophrenia has been associated with better long-term outcome. Low-dose neuroleptic therapy is an effective treatment strategy and the diminished risk of side-effects with this approach may further enhance compliance and outcome.