Superoxide dismutase and cytokines in chronic patients with schizophrenia: association with psychopathology and response to antipsychotics

Objective  Both schizophrenia and oxidative stress have been associated with immune system abnormalities in interleukin-2 and -6 (IL-2; IL-6) and increases in superoxide dismutase (SOD) activity. These abnormalities may improve during antipsychotic drug treatment that reduces symptoms in schizophrenic patients. Materials and methods  Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients who were randomly assigned to 12 weeks of double-blind treatment with risperidone 6 mg/day or haloperidol 20 mg/day. Ratings using the Positive and Negative Syndrome Scale (PANSS) were correlated with blood SOD and serum IL-2 levels. Results  SCH patients who were medication-free for 2 weeks had greater SOD, IL-2, and IL-6 levels than HC. At baseline, these SOD elevations were associated with higher PANSS total scores and the IL-2 elevations with lower PANSS positive symptom scores. The SOD and IL-2 levels in the SCH were also positively correlated. After treatment, PANSS positive symptoms and both SOD and IL-2 showed a significant decrease, but IL-6 showed no change. The SOD and IL-2 reductions were correlated with the reductions in PANSS total score, and SOD reductions also correlated with positive subscore reductions. Females showed these associations more strongly than males. Conclusion  Our results suggest that the dysregulation in the cytokine system and oxidative stress in patients with schizophrenia is implicated in clinical symptoms and is improved at least partially with antipsychotic treatment. The stronger associations in females deserve further study and confirmation.     

Amisulpride: progress and outcomes

Amisulpride is a unique atypical antipsychotic that selectively blocks D2 and D3 receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission, and postsynaptically in the limbic areas, possibly reducing it. Thus dopaminergic over-activity in the frontal cortex, and under-activity in the limbic areas, can be treated simultaneously, alleviating both positive and negative symptoms of schizophrenia, respectively. In acute schizophrenia, amisulpride is at least as effective as haloperidol, with a greater number of patients responding to treatment as determined by Clinical Global Impression (CGI scores (p = 0.014). In addition, amisulpride is associated with a lower incidence of extrapyramidal symptoms (EPS) as determined by Simpson-Angus scores (SAS) when compared with haloperidol (p = 0.0053). Amisulpride showed similar efficacy to risperidone as determined by the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Symptom Score (PANSS) positive subscale; a trend towards greater improvement of negative symptoms as determined by PANSS negative subscale compared with risperidone; and similar levels of EPS. Amisulpride uniquely benefits patients with negative symptoms and is the only antipsychotic to demonstrate efficacy in patients with predominantly negative symptoms. Amisulpride maintains its efficacy when used for medium/long-term treatment as demonstrated in studies of up to 12 months. Amisulpride demonstrates greater improvement in controlling symptoms compared to haloperidol. In terms of the relevance of the effects, a superiority is observed for quality of life, social adaptation and functioning as measured by the Quality of Life Scale (QLS), Clinical Glocal Impression scale (CGI) and Functional Status Questionnaire (FSQ) scales. Amisulpride also has one of the lowest potentials of all the antipsychotic agents for weight gain. The clinical evidence for amisulpride supports its earlier pre-clinical potential, showing it to be an atypical antipsychotic agent with specific clinical advantages.     

Nitric oxide in patients with schizophrenia: the relationship with the severity of illness and the antipsychotic treatment

Objectives: Past studies regarding the relationship between nitric oxide and schizophrenia have reported controversial results. Consequently, the aims of this study are i) to analyze the differences in nitric oxide concentration between patients with schizophrenia and healthy controls, ii) to investigate the influence of antipsychotic treatment on nitric oxide, iii) to correlate nitric oxide concentration with severity of illness, and iv) to investigate the relationship between nitric oxide and any personality disorder. Research design and methods: We recruited 24 patients and 24 controls; the sample was divided into three groups of 8 patients, each according to the pharmacological treatment (haloperidol, olanzapine, or risperidone). The severity of illness was assessed by PANSS and personality traits were evaluated by SCID II. A blood sample was taken to assess the plasma concentration of nitrites and nitrates. Results: Patients presented higher nitrate levels than controls (p < 0.05); subjects under olanzapine reported lower nitrate levels than those treated with risperidone (p < 0.05) or haloperidol (p < 0.001). Nitrate levels were correlated with PANSS total score (rho = 0.748; p < 0.001), but not with SCID II scores. Conclusions: Despite the fact that this study found a correlation between PANSS score and nitrate levels, it is unclear whether nitric oxide is related to the severity of schizophrenia, because nitrate levels are also affected by antipsychotic treatment.     

Use of combinations of antipsychotics: McLean Hospital inpatients, 2002

BACKGROUND: The empirical use of combinations of antipsychotic agents appears to be increasing with little research support for the relative efficacy, safety or cost-effectiveness of this practice. Such treatment was evaluated in hospitalized psychiatric patients. METHODS: Samples of consecutive inpatients treated with > or = 2 ('polytherapy') vs 1 antipsychotic ('monotherapy') were matched on age, sex, diagnosis and admission clinical ratings, and these groups were compared on total daily chlorpromazine-equivalent doses, days in hospital, and changes in clinical ratings between admission and discharge. RESULTS: The study sample included 69 polytherapy and 115 well-matched monotherapy subjects. Despite matching for initial CGI and GAF ratings, polytherapy was associated with high PANSS subscale scores of positive symptoms among affective psychosis, and relatively greater PANSS subscale ratings of excitement-agitation among patients diagnosed with schizophrenia. Estimated clinical improvement during hospitalization was similar among poly- and monotherapy patients, but total daily CPZ-eq doses at discharge averaged twice-greater with polytherapy, and hospitalization lasted 1.5 times longer. CONCLUSIONS: Antipsychotic polytherapy as well as the types of agents combined may reflect clinician responses to particular symptom patterns. The value of specific combinations of antipsychotic agents and their comparison with monotherapies requires specific, prospective, randomized and well-controlled trials that consider matching on clinical characteristics and truly comparable doses across regimens.     

Nitric oxide in patients with schizophrenia: the relationship with the severity of illness and the antipsychotic treatment

Objectives: Past studies regarding the relationship between nitric oxide and schizophrenia have reported controversial results. Consequently, the aims of this study are i) to analyze the differences in nitric oxide concentration between patients with schizophrenia and healthy controls, ii) to investigate the influence of antipsychotic treatment on nitric oxide, iii) to correlate nitric oxide concentration with severity of illness, and iv) to investigate the relationship between nitric oxide and any personality disorder.

Research design and methods: We recruited 24 patients and 24 controls; the sample was divided into three groups of 8 patients, each according to the pharmacological treatment (haloperidol, olanzapine, or risperidone). The severity of illness was assessed by PANSS and personality traits were evaluated by SCID II. A blood sample was taken to assess the plasma concentration of nitrites and nitrates.

Results: Patients presented higher nitrate levels than controls (p < 0.05); subjects under olanzapine reported lower nitrate levels than those treated with risperidone (p < 0.05) or haloperidol (p < 0.001). Nitrate levels were correlated with PANSS total score (rho = 0.748; p < 0.001), but not with SCID II scores.

Conclusions: Despite the fact that this study found a correlation between PANSS score and nitrate levels, it is unclear whether nitric oxide is related to the severity of schizophrenia, because nitrate levels are also affected by antipsychotic treatment.     

Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics.

The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate response of the hypothalamic-pituitary-adrenal (HPA) axis to the stimulatory influence of cytokines and stress-related mediators. Growing evidence suggests that neuro-immune-endocrine crosstalk may be impaired in schizophrenia. We determined the relationship between cortisol, cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6), and symptoms in schizophrenia during treatment with typical and atypical antipsychotic drugs. Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients. SCH were randomly assigned to 12-week treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS). Serum cortisol and IL-2 levels were assayed by radioimmunometric assay, and serum IL-6 levels by quantitative enzyme-linked immunosorbent assay. Following a 2-week washout period, serum levels of cortisol, IL-2, and IL-6 were increased in patients with schizophrenia compared to HC. Elevations in cortisol were associated with increase in both IL-2 and IL-6 in SCH. Moreover, elevations in cortisol were associated with negative symptoms and IL-2 with positive symptoms. In all, 12 weeks of risperidone treatment significantly decreased elevated cortisol and improved negative symptoms, but produced similar effects on IL-2 and IL-6 as well as on positive symptoms compared to haloperidol. The improvement of negative symptoms was related to the change in cortisol. Our results suggest that the imbalance in the HPA axis and cytokine system in patients with SCH is implicated in clinical symptoms, and is improved with atypical antipsychotic treatment.     

Treatment of methamphetamine-induced psychosis: a double-blind randomized controlled trial comparing haloperidol and quetiapine

Rationale

To our knowledge, only a few double-blind randomized controlled trials with antipsychotic drugs have been conducted to examine the treatment of methamphetamine-induced psychosis (MAP).

Objectives

The aims of this study are to compare the antipsychotic and adverse events of quetiapine, an atypical antipsychotic drug, to haloperidol, a standard treatment for primary psychotic disorder, in individuals with MAP.

Methods

Eighty individuals with MAP were randomly assigned into two groups, i.e. treatment with quetiapine (n?=?36) and haloperidol (n?=?44). Sixty-eight patients (85 %) completed the study protocol, i.e. treatment with quetiapine at least 100 mg per day or haloperidol at least 2 mg per day orally once a day for 4 weeks. The doses were increased every 5 days until no psychotic symptom was observed from the Positive and Negative Syndrome Scale (PANSS). Data were analysed by survival analysis with Cox’s proportional regression analysis, general estimating equations and log-rank tests.

Results

Thirty-two (89 %) subjects from the quetiapine group and 37 subjects (84 %) from the haloperidol group met the remission criteria at the end of the study. Baseline PANSS total scores of quetiapine and haloperidol groups were 82.4?±?16.6 and 90.0?±?18.4, respectively (mean?±?SD; p?=?0.06). The change-from-baseline scores were ?47.8 for the quetiapine group and ?53.2 for the haloperidol group. There were no significant differences between the antipsychotic effects (coefficient value?=??2.6, p?=?0.32, 95%CI?=??7.6, 2.5) and the adverse effects of quetiapine and haloperidol.

Conclusions

Quetiapine may be used as an antipsychotic treatment for MAP with comparable therapeutic effects and adverse events to treatment with classical antipsychotic drugs.     

Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study

Rationale There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia.Objectives The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia.Methods Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects.Results Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05).Conclusions Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.     

Improvement of acute exacerbations of schizophrenia with amisulpride: a comparison with haloperidol

Amisulpride is a substituted benzamide with high selectivity for dopaminergic D₂ and D₃ receptors. This study compared 800 mg/day amisulpride and 20 mg/day haloperidol in patients with acute exacerbations of schizophrenia. This multicenter, double-blind trial involved 191 patients allocated, after a 1 to 7-day wash-out period, to amisulpride (n = 95) or haloperidol (n = 96) for 6 weeks. Improvement of mean BPRS total score was 48% for amisulpride and 38% for haloperidol (NS), whereas improvement in the Negative PANSS subscale was greater in the amisulpride group (37%) compared to haloperidol (24%) (P = 0.038). CGI scores showed a higher number of responders in the amisulpride (62%) than in the haloperidol group (44%) (P = 0.014). More extrapyramidal symptoms measured with the Simpson-Angus scale were provoked in the haloperidol group (P = 0.0009). Amisulpride is at least as effective as haloperidol in the treatment of acute exacerbations of schizophrenia, and is more effective in the treatment of negative symptoms whilst causing less parkinsonism. Received: 13 December 1996/Final version: 12 March 1997     

Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis

Haloperidol decanoate is a depot preparation of haloperidol, a commonly used butyrophenone derivative with antipsychotic activity. Haloperidol decanoate has no intrinsic activity: its pharmacodynamic actions are those of haloperidol--primarily that of central antidopamine activity. The monthly administered depot formulation has several clinical and practical advantages over oral haloperidol: better compliance and more predictable absorption; more controlled plasma concentrations; fewer extrapyramidal side effects; less frequent reminders of condition; and reduced medical workload. In open and controlled studies, haloperidol decanoate has produced adequate maintenance or improvement of the condition of patients with psychoses (mainly schizophrenia) when an abrupt change from orally administered haloperidol or other antipsychotic drugs has been instituted. Limited comparative studies indicate that the depot and oral forms of haloperidol are equally effective, and that haloperidol decanoate is at least as effective as depot forms of fluphenazine, pipothiazine, flupenthixol and perphenazine in controlling the symptoms of psychosis. Extrapyramidal side effects and the need for concomitant anti-Parkinsonian drugs may be a problem, but may be less frequent than with oral haloperidol or other depot antipsychotics. Thus, haloperidol decanoate offers a useful alternative in the treatment of psychoses to orally administered haloperidol or to other depot antipsychotic drugs.     

Treatment of the symptoms of schizophrenia: a combined analysis of double-blind studies comparing risperidone with haloperidol and other antipsychotic agents

Combined data on efficacy were available from 12 double-blind short-term (maximum 8 weeks) trials comparing risperidone and other antipsychotics in patients with chronic schizophrenia. Patients received risperidone (n = 1056) or other antipsychotics (n = 703). Haloperidol (n = 473) was the most frequently prescribed other antipsychotic. Efficacy assessments include the Positive and Negative Syndrome Scale (PANSS) total, subscale (positive symptoms, negative symptoms and general psychopathology), cluster (cognitive and affective symptoms) and item (anxiety and hostility) scores. At endpoint, the mean decrease from baseline in PANSS total scores was significantly greater for patients receiving risperidone (-20.9) than other antipsychotics (-16.2; P < 0.001), or the subset receiving haloperidol (-14.3; P < 0.001). Risperidone-treated patients showed a significantly greater decrease in the positive (P < 0.01), negative (P < 0.05) and general psychopathology (P < 0.001) scores than patients receiving other antipsychotics or haloperidol. Scores for cognition, affective symptoms, anxiety and hostility each improved significantly (P < 0.05) more for patients receiving risperidone than those receiving other antipsychotics or haloperidol. Efficacy data on patients with an acute exacerbation were available from seven trials (risperidone n = 372, other antipsychotics n = 285, including haloperidol n = 120). At endpoint, the mean decrease from baseline in PANSS total scores was significantly greater for patients receiving risperidone (-24.7) than other antipsychotics (-19.8, P < 0.01) including haloperidol (-19.8, P < 0.05). Risperidone-treated patients also showed a greater decrease in positive symptom scores (-7.8) than those receiving other antipsychotics (-6.3; P < 0.01) or haloperidol (-7.1). A > or = 20% reduction in PANSS total score with risperidone, haloperidol and other antipsychotics was achieved by 65.9%, 54.3% and 54.9%, respectively; a > or = 30% PANSS reduction by 54.0%, 46.6% and 46.5% of patients, respectively; and a > or = 40% reduction by 43.8%, 33.7% and 34.4% of patients, respectively. These findings are consistent with earlier findings that show risperidone is more efficacious than haloperidol for reducing the symptoms of schizophrenia.     

Differential efficacy of risperidone versus haloperidol in psychopathological subtypes of subchronic schizophrenia

The aim of this study was to evaluate the efficacy and tolerability of risperidone versus haloperidol in subchronic schizophrenia, using psychopathological subgroups of patients with negative or positive and mixed symptoms to analyse the possible differential efficacy of the drugs. A total of 33 patients diagnosed using DSM-IV criteria entered the 6 week double-blind study with either risperidone or haloperidol 5 mg/day. Twenty-nine patients completed at least 2 weeks of treatment and entered the last observation carried-forward analysis. Both treatments were effective in reducing total scores and positive and negative subscale scores on the Positive and Negative Scale for Schizophrenia (PANSS), with a significantly better extrapyramidal profile in the risperidone-treated group. When analysis was repeated in each treatment group by psychopathological subtype (negative vs positive-mixed subgroups based on the PANSS composite index), risperidone was significantly superior to haloperidol in the intention to treat analysis in the negative subgroup. Repeated measures multivariate analysis of variance showed a significantly greater improvement in the PANSS negative subscale scores of risperidone-treated patients in the negative subgroup and a significant improvement in the PANSS positive subscale scores in both psychopathological subtypes. Haloperidol was significantly effective only in reducing positive symptoms in the positive subtype. Our results indicate that risperidone may be proposed for first-line treatment of subchronic schizophrenia, in particular the negative subtype. Copyright 2001 John Wiley & Sons, Ltd.     

To what extent do the PANSS and CGI-S overlap?

BACKGROUND: The Positive and Negative Symptom Scale (PANSS) and Clinical Global Impression (CGI-S) item for severity are used together to measure severity of psychotic illness. PANSS is the "gold standard" measure of efficacy, but it is not always feasible to use, yet the CGI-S requires validation. OBJECTIVES: To examine the overlap between PANSS and CGI-S. METHODS: The overlap of the PANSS and CGI-S were examined using data from 7 large antipsychotic clinical trials (n = 4287). RESULTS: Regression analysis identified 21% to 60% overlap of the measures depending on the trial and measurement point. The pooled study mean PANSS value corresponding with a CGI-S of 2, 3, and 4 were 67.1 (n = 799), 79.6 (n = 1645), and 92.4 (n = 1056), respectively. A decrease of 1 on the CGI-S corresponded to a 20% decline on the PANSS. Of the 37 planned comparisons in these studies, there was an agreement between the PANSS and CGI-S on change from baseline to end point on 32 comparisons and on dichotomized change variables (PANSS > or =-20% and CGI-S > or =-1 point) on 31 comparisons. The differences in the remaining comparisons would not have changed the conclusions of the studies. The positive and disorganized PANSS scales were the most closely related to the CGI-S, followed by hostility and negative scale with almost no association with anxiety/depression. CONCLUSIONS: The CGI-S and PANSS are correlated but are not synonymous. Both measures, however, show substantial agreement in detecting change, and the CGI-S shows overlap with the core symptoms of schizophrenia.     

Haloperidol-induced extrapyramidal reaction: lack of protective effect by vitamin E

Haloperidol treatment has been shown to produce oxidative stress in patients with acute psychosis. Oxidative stress has also been implicated in the extrapyramidal symptoms (EPS) produced by haloperidol. Supporting the oxidative stress hypothesis, vitamin E (antioxidant) has demonstrated therapeutic efficacy in idiopathic parkinsonism. The prophylactic efficacy of vitamin E (antioxidant) on haloperidol-induced EPS was examined in a randomized controlled trial. The sample consisted of 24 acute psychotic patients hospitalized for a 2-week trial. All patients received oral haloperidol 10 mg/day. The sample was equally randomized to receive either haloperidol alone or haloperidol + vitamin E (3200 IU/day). EPS was rated at recruitment, both live and with video records, and on days 3, 7, 10 and 14. Psychopathology was rated at recruitment and weekly thereafter. Vitamin E had no prophylactic effect on drug-induced EPS, though it did not interfere with the therapeutic efficacy of haloperidol. Received: 15 October 1997/Final version: 15 May 1998     

Risperidone: a review of its use in the management of the behavioural and psychological symptoms of dementia

Risperidone is a benzisoxazole derivative which has proven efficacy against the positive and negative symptoms of schizophrenia. It has more recently been investigated and shown efficacy as a treatment for the behavioural and psychological symptoms associated with dementia in the elderly. Risperidone has pharmacological properties resembling those of the atypical antipsychotic clozapine and an improved tolerability profile compared with the conventional antipsychotic haloperidol. Risperidone has antagonistic activity primarily at serotonin 5-HT2A and dopamine D2 receptors. In the first 2 large, well controlled trials of an antipsychotic agent used in the treatment of elderly patients with Alzheimer's dementia, vascular dementia or mixed dementia, risperidone 1 mg/day was at least as effective as haloperidol and superior to placebo, as assessed by the rating scales for global behaviour, aggression and psychosis. In extension phases of the 2 trials, clinical benefits were maintained for treatment periods of up to 1 year, with an incidence rate of tardive dyskinesia (2.6%) one-tenth of that seen with conventional antipsychotics. Risperidone, administered at a low dosage of 1 mg/day was associated with fewer extrapyramidal symptoms compared with haloperidol in elderly patients. Risperidone was well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results. Conclusion: The efficacy of risperidone has been demonstrated in the treatment of the behavioural and psychological symptoms associated with dementia in the elderly. Preliminary results from 1-year extension studies confirm the favourable efficacy and tolerability profile of risperidone 1 mg/day. Although head to head studies with other atypical antipsychotic agents are required and the long term use of the drug requires clarification, risperidone represents a generally well tolerated and effective treatment in the management of dementia-associated behavioural and psychological symptoms in the elderly.     

A comparison of the effects of quetiapine ('seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group

Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.     

Risperidone versus haloperidol in the treatment of acute exacerbations of chronic inpatients with schizophrenia: a randomized double-blind study.

The purpose of this study was to compare the efficacy and safety of risperidone and haloperidol in treatment-resistant chronic schizophrenic patients. Subjects (n = 78) who met DSM-III criteria for schizophrenia were randomly assigned to receive 6 mg/day of risperidone or 20 mg/day of haloperidol for 12 weeks. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS), and side-effects with the Treatment Emergent Symptom Scale (TESS). Risperidone produced a mean 39.8 +/- 24.1% reduction in total PANSS score compared to a mean 28.3 + 19.4% reduction in the haloperidol group (P < 0.05). Analysis of changes for the three subscores of the PANSS revealed that the general psychopathology and negative subscores were significantly improved in the risperidone group compared to the haloperidol group. As for the side-effects, the risperidone group showed a significantly lower TESS total score, as well as nervous system symptoms subscore and cardiovascular symptoms subscore, compared to the haloperidol group. Risperidone appears to be a more effective and better tolerated antipsychotic drug in treatment-refractory Chinese schizophrenia than haloperidol.     

Activation of midline thalamic nuclei by antipsychotic drugs

The thalamus has been proposed as a site which may be involved in the production of the syndrome of schizophrenia and the response of schizophrenic symptoms to treatment. These studies test whether, consistent with this hypothesis, the activation of thalamic nuclei is a shared property of neuroleptic antipsychotic drugs. Rats were given single doses of the typical high and low potency neuroleptics haloperidol (1 mg/kg) and chlorpromazine (20 mg/kg), the atypical neuroleptics thiroridazine (20 mg/kg) and clozapine (20 mg/kg), the specific dopamine antagonist raclopride (3 mg/kg), the mixed dopamine/serotonin antagonist risperidone (3 mg/kg) or drug-free vehicle. Increased expression of Fos-like protein was utilized as a marker of cellular activation. All drugs tested, including typical and atypical antipsychotic agents, led to similar effects on the midline thalamic paraventricular, centromedian and rhomboid nuclei and the nucleus reuniens. These results suggest that midline thalamic nuclei may participate in neural circuits mediating some of the shared effects of antipsychotic drugs. Received: 9 January 1997/Final verion: 13 June 1997     

Plasma level monitoring of antipsychotic drugs. Clinical utility

The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some studies have reported a relationship between therapeutic response and serum antipsychotic drug 'concentrations' as measured using the radioreceptor assay (RRA) method, which measures dopamine receptor-blocking activity in plasma. Most studies, however, have failed to demonstrate such a relationship, and the RRA does not seem to provide the generally useful tool for plasma concentration monitoring of antipsychotic drugs that was hoped for initially. A lack of correlation between dopamine receptor-blocking activity in plasma and therapeutic response may be due to differences in the blood-brain distribution of both antipsychotic drugs and their active metabolites. Chemical assay methods (e.g. GLC and HPLC) have been used in studies which examined the relationships between therapeutic response and antipsychotic drug concentrations in red blood cells and in plasma. It seems that for these drugs, measuring red blood cell concentrations does not offer any significant advantage over measuring plasma concentrations. Reasonably controlled studies of plasma concentration-response relationships using randomly allocated, fixed dosages of chlorpromazine, fluphenazine, haloperidol, perphenazine, sulpiride, thioridazine and thiothixene have been published but often involve relatively few patients. A correlation between therapeutic response and plasma concentrations of thioridazine and its metabolites has not been demonstrated, and plasma level monitoring of thioridazine and its metabolites therefore appears to have no clinical value. Clinical behavioural deterioration concomitant with high plasma concentrations of chlorpromazine and haloperidol have been reported. A dosage reduction might be considered after 2 to 4 weeks' treatment in non-responders who have plasma chlorpromazine concentrations above 100 to 150 micrograms/L or plasma haloperidol concentrations above 20 to 30 micrograms/L. Non-responders and good responders to chlorpromazine treatment, however, have plasma drug concentrations in the same range, and a therapeutic range of plasma chlorpromazine levels has not been defined. Therapeutic plasma haloperidol concentrations (i.e. 'window') in the range of 5 to 20 micrograms/L have been reported by some investigators, but others have found no such relationship.(ABSTRACT TRUNCATED AT 400 WORDS)     

Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia

Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. The purpose of the present study was to determine whether PCP can induce similar behavioural effects in rats and whether these effects can be alleviated by neuroleptic drug treatment. Rats were tested in the social interaction test, and their behaviour was quantified by an automated video-tracking system and manual scorings of stereotyped behaviour and ataxia. The behavioural effects of different dose- and administration regimes of PCP were initially determined, and it was found that PCP dose-dependently induced stereotyped behaviour and social isolation in the rats. Comparison to clinical studies suggests that these behaviours correspond to certain aspects of the positive and negative symptoms, respectively, of a PCP psychosis in humans. Subsequently, the effects of 3 or 21 days of administration of the antipsychotic drugs haloperidol or clozapine on the behaviour of either vehicle- or PCP-treated rats were determined. Haloperidol did not produce a selective antagonism of PCP, whereas chronic clozapine selectively inhibited the PCP-induced stereotyped behaviour and social isolation. These effects of haloperidol and clozapine suggest that this animal model can determine the effects of neuroleptic drugs on positive and negative symptoms, onset of action, and side-effect profile, including effects on the motor system. Together these data suggest that this may be a possible animal model of the positive and negative symptoms of schizophrenia.