Shared decision making and long-term outcome in schizophrenia treatment. The effect of fluphenazine upon social and vocational functioning in remitted schizophrenics. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Effectiveness of psychoeducational intervention for rural Chinese families experiencing schizophrenia--a randomised controlled trial. Long-acting oral vs injectable antipsychotic drugs in schizophrenics: a one-year double-blind comparison in multiple episode schizophrenics. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study. The Bergen District Nursing Home Study. Comparative effectiveness of fluphenazine decanoate injections every 2 weeks versus every 6 weeks. One-year, low-dose neuroleptic study of in-patients with chronic schizophrenia characterised by persistent negative symptoms. Amisulpride v. haloperidol. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Cognition, functioning and quality of life in schizophrenia treatment: results of a one-year randomized controlled trial of olanzapine and quetiapine. Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial. The risks and benefits of clozapine versus chlorpromazine. Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. The European First Episode Schizophrenia Trial (EUFEST): rationale and design of the trial. Antipsychotic prophylaxis is needed after remission from a first psychotic episode in schizophrenia patients: results from an aborted randomised trial. Are there schizophrenics for whom drugs may be unnecessary or contraindicated? A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. [Clinical study of shuizhi-dahuang mixture in treating schizophrenics with blood stasis syndrome]. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. A cognitive/behavioral group intervention for weight loss in patients treated with atypical antipsychotics. A one-year double-blind comparison of long-acting oral (penfluridol) versus long-acting injectable (fluphenazine decanoate) antipsychotic drugs in multiple-episode schizophrenics. Issues that may determine the outcome of antipsychotic trials: industry sponsorship and extrapyramidal side effect. Diazepam treatment of early signs of exacerbation in schizophrenia. Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine. Quetiapine is not associated with increase in prolactin secretion in contrast to haloperidol. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. Olanzapine versus risperidone in the treatment of post-psychotic depression in schizophrenic patients. Clozapine and "high-dose" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes. Efficacy of antipsychotic medications in behaviorally disturbed dementia patients. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Risperidone, quetiapine, and fluphenazine in the treatment of patients with therapy-refractory schizophrenia. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Penfluridol: a long acting oral antipsychotic drug. A placebo controlled trial of bupropion for smoking cessation in schizophrenia. Clozapine versus chlorpromazine for the treatment of schizophrenia: preliminary results from a double-blind study. Efficacy of risperidone versus olanzapine in patients with schizophrenia previously on chronic conventional antipsychotic therapy: a switch study. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics. Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination. A double-blind, randomized comparative trial of amisulpride versus olanzapine for 6 months in the treatment of schizophrenia. The treatment of acute psychosis without neuroleptics: six-week psychopathology outcome data from The Soteria Project. Trial of brief intermittent neuroleptic prophylaxis for selected schizophrenic outpatients: clinical and social outcome at two years. Haloperidol decanoate and flupenthixol decanoate in schizophrenia. A long-term double-blind cross-over comparison. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Addition of lithium to haloperidol in non-affective, antipsychotic non-responsive schizophrenia: a double blind, placebo controlled, parallel design clinical trial. Effect of switching to atypical antipsychotics on memory in patients with chronic schizophrenia. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. A double-blind clinical trial of mianserin versus amitriptyline: differentiation by adverse symptomatology. Long-term follow-up results of a randomized drug abuse prevention trial in a white middle-class population. Preventing school failure, drug use, and delinquency among low-income children: long-term intervention in elementary schools. An experimental intervention with families of substance abusers: one-year follow-up of the focus on families project.
Compliance with antipsychotic medication is a major issue in schizophrenia treatment, and noncompliance with antipsychotic treatment is closely related to relapse and rehospitalization. An enhanced involvement of patients with schizophrenia in treatment decisions ("shared decision making") is expected to improve long-term compliance and reduce rehospitalizations. The aim of the present analysis was to study whether shared decision making (SDM) in antipsychotic drug choice would influence long-term outcome.
                From February 2003 to January 2004, psychiatric state hospital inpatients with a diagnosis of schizophrenia (ICD-10; N = 107) were recruited for the trial using a cluster-randomized controlled design. An SDM program on antipsychotic drug choice consisting of a decision aid and a planning talk between patient and physician was compared with routine care with respect to long-term compliance and rehospitalizations (6-month and 18-month follow-up).
                On the whole, we found high rates of noncompliance and rehospitalization. There were no differences between intervention and control groups in the univariate analyses. However, when controlling for confounding factors in a multivariate analysis, there was a positive trend (p = .08) that patients in the SDM intervention had fewer rehospitalizations. Additionally, a higher desire of the patient for autonomy and better knowledge at discharge were associated with higher hospitalization rates.
                The intervention studied showed a positive trend but no clear beneficial effect on long-term outcomes. A more thorough implementation of SDM (e.g., iterative administration of decision aid) might yield larger effects. Those patients with higher participation preferences are at higher risk for poor treatment outcomes and therefore require special attention. Strategies to match these patients' needs might improve compliance and long-term outcomes. Thirty-six remitted schizophrenics who participated in an outpatient study of fluphenazine decanoate or oral fluphenazine vs placebo given for a year were examined for the effect of drug treatment upon social and vocational functioning. Only the period prior to any clinical relapse was evaluated. We found no difference between those on drug or placebo, and conclude that antipsychotic drugs, at least in the context of an aftercare clinic offering a rich spectrum of nonpharmacological services, and when combined with antiparkinson medication, do not interfere with social and vocational functioning. Data from 12-week placebo-controlled trials have led to mounting concerns about increased mortality in patients with Alzheimer's disease (AD) who are prescribed antipsychotics; however, there are no mortality data from long-term placebo-controlled trials. We aimed to assess whether continued treatment with antipsychotics in people with AD is associated with an increased risk of mortality.
                Between October, 2001, and December, 2004, patients with AD who resided in care facilities in the UK were enrolled into a randomised, placebo-controlled, parallel, two-group treatment discontinuation trial. Participants were randomly assigned to continue with their antipsychotic treatment (thioridazine, chlorpromazine, haloperidol, trifluoperazine, or risperidone) for 12 months or to switch their medication to an oral placebo. The primary outcome was mortality at 12 months. An additional follow-up telephone assessment was done to establish whether each participant was still alive 24 months after the enrollment of the last participant (range 24-54 months). Causes of death were obtained from death certificates. Analysis was by intention to treat (ITT) and modified intention to treat (mITT). This trial is registered with the Cochrane Central Registry of Controlled Trials/National Research Register, number ISRCTN33368770.
                165 patients were randomised (83 to continue antipsychotic treatment and 82 to placebo), of whom 128 (78%) started treatment (64 continued with their treatment and 64 received placebo). There was a reduction in survival in the patients who continued to receive antipsychotics compared with those who received placebo. Cumulative probability of survival during the 12 months was 70% (95% CI 58-80%) in the continue treatment group versus 77% (64-85%) in the placebo group for the mITT population. Kaplan-Meier estimates of mortality for the whole study period showed a significantly increased risk of mortality for patients who were allocated to continue antipsychotic treatment compared with those allocated to placebo (mITT log rank p=0.03; ITT p=0.02). The hazard ratio for the mITT group was 0.58 (95% CI 0.35 to 0.95) and 0.58 (0.36 to 0.92) for the ITT population. The more pronounced differences between groups during periods of follow up longer than 12 months were evident at specific timepoints (24-month survival 46%vs 71%; 36-month survival 30%vs 59%).
                There is an increased long-term risk of mortality in patients with AD who are prescribed antipsychotic medication; these results further highlight the need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in these patients.
                UK Alzheimer's Research Trust. The aim of this study was to explore the characteristics and efficacy of psychoeducational family intervention for persons with schizophrenia in rural China.
                A cluster randomised controlled trial of psychoeducational family intervention for families experiencing schizophrenia (three groups, 326 cases) was conducted in Xinjin County, Chengdu. Treatment groups consisted of family intervention and medication, medication alone, and a control.
                The results showed a gain in knowledge, a change in the relatives' caring attitudes towards the patients, and an increase in treatment compliance in the psychoeducational family intervention group (p < 0.05, 0.001). Most importantly, the relapse rate over 9 months in this group (16.3 %) was half that of the drug-only group (37.8 %), and just over one-quarter of that of the control group (61.5 %) (p < 0.05). Antipsychotic drug treatment and families' attitudes towards patients after the 9-month follow-up were significantly associated with clinical outcome (p < 0.05).
                In rural China, family intervention should focus on improving the relatives' recognition of illness, the caring attitude towards the patients, treatment compliance, relapse prevention, and the training of the patients' social functioning. This trial, one of the largest in the literature, has shown that psychoeducational family intervention is effective and suitable for psychiatric rehabilitation in Chinese rural communities. Sixty patients meeting the criteria established for schizophrenia who attained a clinical plateau following hospital discharge were randomized to receive for one year either penfluridol, 20 to 160 mg orally once each week, or fluphenazine decanoate, 0.5 to 4 ml every two weeks. The relapse rate for both treatments was low and equal. The rate of recurrence of psychosis for patients receiving penfluridol was 7% and for those receiving fluphenazine decanoate 10%. A retrospective comparison of the penfluridol group was made to a similar group of patients assigned to placebo in an earlier study. Placebo-treated patients had a relapse rate of 68%. Penfluridol patients had statistically fewer psychotic relapses. Questions about the possible carcinogenicity of penfluridol in animals will have to be resolved before it can be widely used. This study demonstrates the feasibility of using an oral, long-acting antipsychotic agent. It would be a useful psychopharmacologic addition in the treatment of outpatient schizophrenics. Schizophrenic patients have high rates of cigarette smoking. The authors compared the outcomes of two group psychotherapy programs for smoking cessation in patients with schizophrenia or schizoaffective disorder who were also treated with the nicotine transdermal patch and with either atypical or typical antipsychotic medications.
                Forty-five subjects were randomly assigned to 1) the group therapy program of the American Lung Association (N=17) or 2) a specialized group therapy program for smokers with schizophrenia (N=28) that emphasized motivational enhancement, relapse prevention, social skills training, and psychoeducation. All subjects participated in 10 weeks of treatment with the nicotine transdermal patch (21 mg/day) and 10 weekly group therapy sessions and continued to receive their prestudy atypical (N=18) or typical (N=27) antipsychotic medications. Outcome variables included treatment retention, rate of smoking abstinence, and expired-breath carbon monoxide level.
                Smoking abstinence rates did not differ in the two group therapy programs. However, atypical antipsychotic agents, in combination with the nicotine transdermal patch, significantly enhanced the rate of smoking cessation (55.6% in the atypical agent group versus 22.2% in the typical group), which was reflected by a significant effect of atypical versus typical agents on carbon monoxide levels. Risperidone and olanzapine were associated with the highest quit rates.
                The results suggest that 1) smoking cessation rates with the nicotine transdermal patch are modest in schizophrenia, 2) specialized group therapy for schizophrenic patients is not significantly different from American Lung Association group therapy in its effect on smoking cessation, and 3) atypical agents may be superior to typical agents in combination with the nicotine transdermal patch for smoking cessation in schizophrenia. The objectives of this randomized clinical trial were to investigate the impact of the discontinuation of long-term antipsychotics in residents with dementia in chronic care institutions and to identify clinical predictors of safe discontinuation. Subjects included 34 residents with dementia who were on antipsychotics for more than 6 months and whose behavior was currently stable. Subjects were randomized to either continue receiving their regular dosage of antipsychotics or to receive placebo for 6 months. Early withdrawal from the study was not statistically different between the groups (relative risk [RR] = 1.57, 95% confidence interval [CI] 0.76-3.26), and though not significantly different, subjects in the placebo group were more likely to be withdrawn from the study because of worsening behavior (RR = 1.25, 95% Cl 0.33-4.76). Three subjects in the placebo group were withdrawn from the study due to worsening of extrapyramidal symptoms. The active treatment group had more behavioral problems (e.g., physical aggression towards others, p < .05) compared to the placebo group. The placebo group developed more apathy, but balancing this outcome was a relative improvement in cognitive functioning. Baseline antipsychotic dose was predictive of behavioral worsening upon discontinuation of long-term antipsychotic drugs. The primary limitation of the study was the small sample size. In conclusion, a trial of discontinuation of antipsychotics should be considered in this population. To explore the effect on sleep/wake activity and on behavioral and psychological symptoms of the withdrawal of antipsychotic medications from nursing home (NH) patients with dementia.
                Randomized, placebo-controlled, double-blind trial.
                NHs in Bergen, Norway.
                Thirty patients (mean age 83.5) taking haloperidol, risperidone, or olanzapine for nonpsychotic symptoms. Intervention: Study participants were randomly assigned to withdrawal (intervention group) or continued treatment with antipsychotic medications (reference group) for 4 consecutive weeks.
                Behavioral rating using the Neuropsychiatric Inventory Questionnaire (NPI-Q) and actigraphy.
                After antipsychotic withdrawal, behavioral scores remained stable or improved in 11 of 15 patients, whereas four had worsening scores. Actigraphy revealed decreased sleep efficiency after drug discontinuation and increased 24-hour and night activity in both groups. Actigraphy records of nighttime and daytime activity indicated sleep problems and restlessness, in terms of the NPI-Q. One patient was restarted on antipsychotics.
                Antipsychotic drug withdrawal affected activity and sleep efficiency over the short term. Increases in total activity and impaired sleep quality after drug discontinuation should be monitored, because the long-term effect of these changes is not known. The NPI-Q and actigraphy are feasible tools that disclose relevant changes occurring during antipsychotic withdrawal in NH patients with dementia. Their use in clinical practice should be substantiated by larger studies. Dose reduction strategies for the maintenance treatment of schizophrenia are designed to maintain the benefits of antipsychotic drug therapy while reducing risks. Previous strategies with decanoate preparations have been based on the use of lower doses per injection to achieve dose reduction; these strategies have achieved dose reduction but have resulted in some increase in symptoms. The authors tested a new dose reduction approach: increasing the interval between injections during intramuscular decanoate antipsychotic treatment.
                Fifty outpatients with schizophrenia or schizoaffective disorder were randomly assigned to receive 25 mg of fluphenazine decanoate intramuscularly either every 2 weeks or every 6 weeks for 54 weeks in a double-blind design.
                The two dose regimens did not differ significantly in relapse, symptom, or side effect measures. The every-6-weeks regimen was associated with a significant reduction in total antipsychotic exposure.
                The use of injections every 6 weeks instead of every 2 weeks may increase compliance and improve patients' comfort as well as decrease cumulative antipsychotic exposure, without increasing relapse rates or symptoms. Amisulpride is a potent substituted benzamide antipsychotic drug claimed to improve the negative symptoms of schizophrenia, particularly at low dosage.
                Sixty long-term in-patients with schizophrenia and selected for predominant negative symptoms were randomised to receive either haloperidol or amisulpride. Over a year there was systematic dose reduction, as symptoms allowed.
                There were no significant differences between the treatment groups in the proportion receiving low-dose treatment, the control of positive symptoms, or ratings of social behaviour, side-effects or tardive dyskinesia. For negative symptoms, there were consistent but non-significant trends in favour of amisulpride. The amisulpride patients required significantly less anticholinergic medication.
                In chronically-hospitalised in-patients with schizophrenia characterised by persistent negative symptoms, amisulpride was a well-tolerated maintenance antipsychotic medication. The drug had only a limited effect in reducing negative symptoms, which were relatively stable, enduring phenomena in this sample, despite dosage reduction. In many parts of the world, second-generation antipsychotics have largely replaced typical antipsychotics as the treatment of choice for schizophrenia. Consequently, trials comparing two drugs of this class--so-called head-to-head studies--are gaining in relevance. The authors reviewed results of head-to-head studies of second-generation antipsychotics funded by pharmaceutical companies to determine if a relationship existed between the sponsor of the trial and the drug favored in the study's overall outcome.
                The authors identified head-to-head comparison studies of second-generation antipsychotics through a MEDLINE search for the period from 1966 to September 2003 and identified additional head-to-head studies from selected conference proceedings for the period from 1999 to February 2004. The abstracts of all studies fully or partly funded by pharmaceutical companies were modified to mask the names and doses of the drugs used in the trial, and two physicians blinded to the study sponsor reviewed the abstracts and independently rated which drug was favored by the overall outcome measures. Two authors who were not blinded to the study sponsor reviewed the entire report of each study for sources of bias that could have affected the results in favor of the sponsor's drug.
                Of the 42 reports identified by the authors, 33 were sponsored by a pharmaceutical company. In 90.0% of the studies, the reported overall outcome was in favor of the sponsor's drug. This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared. Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings.
                Some sources of bias may limit the validity of head-to-head comparison studies of second-generation antipsychotics. Because most of the sources of bias identified in this review were subtle rather than compelling, the clinical usefulness of future trials may benefit from minor modifications to help avoid bias. The authors make a number of concrete suggestions for ways in which potential sources of bias can be addressed by study initiators, peer reviewers of studies under consideration for publication, and readers of published studies. Cognitive deficits are recognized as a critical determinant of functional outcomes in schizophrenia; and second generation antipsychotic drugs have been touted for their potential to enhance cognitive functioning and community tenure.
                The study examined the relative merits of olanzapine and quetiapine in improving cognitive deficits and enhancing psychosocial functioning in a sample of community dwelling adults previously treated with first generation antipsychotic drugs for schizophrenia.
                In a prospective, rater-blinded study, 86 participants were randomized to receive either olanzapine or quetiapine, and assessed at baseline and after 3, 6, 9 and 12 months. Outcome measures included, besides symptoms and side effects rating scales, the subjective scale to investigate cognition in schizophrenia (SSTICS), a computer-assisted cognitive test battery (COGLAB), the sickness impact profile (SIP), the global assessment of functioning (GAF) scale, and the drug attitude inventory (DAI).
                Both olanzapine and quetiapine were equally effective in improving symptom severity and decreasing the neurological side effects. Quetiapine was significantly better tolerated (p=0.002), improved self-rated cognitive dysfunction (p=0.002) and subjects' performance on selected neurocognitive tasks (p=0.01). Olanzapine use was associated with greater symptom stability, fewer drop outs (p=0.01) and frequent metabolic aberrations (p=0.001). The accrued benefits of drug therapy, however, were not reflected as significant gains in daily functioning and quality of life.
                Quetiapine is noted to have specific cognition enhancing properties in schizophrenia that warrants further exploration. The observed clinical and cognitive benefits associated with quetiapine may likely be attributable to its loose binding to, and fast dissociation from the dopamine receptors. Olanzapine has proved to be a reliable antipsychotic drug with a greater liability to cause metabolic abnormalities. To study rates of relapse in remitted patients with first episode psychosis who either continued or discontinued antipsychotic drugs after at least one year of maintenance treatment.
                12 month randomised, double blind, placebo controlled trial.
                Early psychosis outpatient clinics in Hong Kong.
                178 patients with first episode psychosis who had received at least one year of antipsychotic drug treatment between September 2003 and July 2006 and had no positive symptoms of psychosis.
                Patients received either maintenance treatment with quetiapine (400 mg/day) or placebo and were followed up for the next 12 months or until a relapse occurred.
                Relapse assessed monthly and defined as re-emergence of psychotic symptoms (delusions, conceptual disorganisation, hallucinations, suspiciousness, and unusual thought content) according to predefined thresholds.
                178 patients were randomised (89 to quetiapine and 89 to placebo). The Kaplan-Meier estimate of the risk of relapse at 12 months was 41% (95% confidence interval 29% to 53%) for the quetiapine group and 79% (68% to 90%) for the placebo group (P<0.001). Although quetiapine was generally well tolerated, the rate of discontinuation due to adverse or serious adverse events was greater in the quetiapine group (18%; 16/89) than in the placebo group (8%; 7/89) (relative risk 2.29, 95% confidence interval 0.99 to 5.28; chi(2)=3.20, df=1; P=0.07).
                In a group of asymptomatic patients with first episode psychosis and at least one year of previous antipsychotic drug treatment, maintenance treatment with quetiapine compared with placebo resulted in a substantially lower rate of relapse during the following year. Trial registration Clinical trials NCT00334035. Clozapine is an atypical antipsychotic drug with reduced risk of unwanted neurological effects in comparison with other drugs. In this multicenter study, 151 hospitalized schizophrenic patients were randomly assigned to treatment under double-blind conditions to assess the antipsychotic efficacy and safety of clozapine versus chlorpromazine. All patients exhibited tardive dyskinesia or other extrapyramidal side effects associated with at least two prior neuroleptics. Eleven patients were dropped from treatment due to extrapyramidal symptoms while being treated with chlorpromazine; only one clozapine patient's treatment was terminated for this reason. Clozapine patients exhibited clinical improvement superior to that of chlorpromazine patients as assessed by the Brief Psychiatric Rating and Clinical Global Impression scales. These results suggest that clozapine is well tolerated and may be therapeutically superior to chlorpromazine in treating psychotic behavior. Agranulocytosis potential can be minimized by frequent white blood cell counts and removing nonresponding patients from treatment prior to the peak risk period (months 2 through 6). Clozapine and risperidone were the first two "second-generation" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents.
                After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents.
                Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone.
                The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed. Few long-term studies have compared the efficacy and safety of typical and atypical antipsychotic medications directly in patients with a first episode of psychosis who met the criteria for schizophrenia or a related psychotic disorder. This study compared the acute and long-term effectiveness of haloperidol with that of olanzapine in patients with first-episode psychosis in a large, controlled clinical trial.
                Patients with first-episode psychosis (N=263) were randomly assigned under double-blind conditions to receive haloperidol or olanzapine and were followed for up to 104 weeks. Domains measured included psychopathology, psychosocial variables, neurocognitive functioning, and brain morphology and metabolism. This report presents data from clinical measures of treatment response and safety data from the 12-week acute treatment phase.
                Haloperidol and olanzapine were associated with substantial and comparable baseline-to-endpoint reductions in symptom severity, which did not differ significantly in last-observation-carried-forward analyses. However, in a mixed-model analysis, olanzapine-treated subjects had significantly greater decreases in symptom severity as measured by the Positive and Negative Syndrome Scale total score and negative and general scales and by the Montgomery-Asberg Depression Rating Scale but not as measured by the Positive and Negative Syndrome Scale positive scale and by the Clinical Global Impression severity rating. Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients. Overall, significantly more olanzapine-treated subjects than haloperidol-treated subjects completed the 12-week acute phase of the study (67% versus 54%).
                As expected on the basis of previous studies, both olanzapine and haloperidol were effective in the acute reduction of psychopathological symptoms in this group of patients with first-episode psychosis. However, olanzapine had several relative advantages in therapeutic response. Although the nature of adverse events differed between the two agents, retention in the study was greater with olanzapine. Retention in treatment is important in this patient population, given their risk of relapse. Longer-term results are needed to determine whether treatment with atypical antipsychotics results in superior outcomes for a first episode of schizophrenia. Most studies comparing second generation antipsychotics with classical neuroleptics have been conducted in more or less chronic schizophrenia patients. Such studies were usually conducted in highly selected samples, and were generally designed and financed by the manufacturer of the drug tested. These and other facts have stimulated discussions regarding the effectiveness of the new generation of antipsychotics.
                The aim of the European First Episode Schizophrenia Trial (EUFEST) is to compare treatment with amisulpride, quetiapine, olanzapine and ziprasidone to a low dose of haloperidol in an unselected sample of first episode schizophrenia patients with minimal prior exposure to antipsychotics.
                500 patients between the ages of 18-40 meeting DSM-IV criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder are randomly allocated to one year of treatment with one of the drugs under study. The primary outcome measure is retention in treatment, defined as time to discontinuation of study drug. Loss of retention can be the result of insufficient clinical effect, or lack of tolerability or acceptance. Secondary measures include changes in different dimensions of psychopathology, side effects, compliance, social needs, quality of life, substance abuse and cognitive functions.
                At present, more than 400 patients have been recruited and randomized in the following countries: Austria, Belgium, Bulgaria, Czech Republic, Germany, France, Israel, Italy, the Netherlands, Poland, Rumania, Spain, Sweden and Switzerland: The study should be finished by the end of 2006 and it is expected that results will yield relevant clinical information with regard to the effectiveness of the second generation antipsychotics. This effort represents the first independently designed trans-European schizophrenia treatment trial. To assess the effect of withdrawal of antipsychotic treatment on relapse risk in remitted first-episode schizophrenia patients.
                First-episode 1-year stable and remitted outpatients with a schizophrenic disorder were randomly allocated to continuation of their antipsychotic regimen for at least 6 months (N = 9), or gradual withdrawal (N = 11). Primary outcome was the difference in cumulative relapse-free survival at 9 months.
                Recruitment was terminated prematurely on 26 October 2005. The cumulative relapse-free survival was 88% (SE = 0.12) in the continuation and 18% (SE = 0.12) in the discontinuation group (P = 0.001) at 9 months follow-up.
                Discontinuation of antipsychotic medication markedly increases the risk of relapse in stable remitted first-episode schizophrenia patients. In future studies the topics of safety monitoring and sampling of patients should receive extra attention. This study reports that there are schizophrenics who do relatively well long term without the routine or continuous use of antipsychotic medication. Specially selected young males undergoing an acute schizophrenic episode were followed, after hospitalization, for up to three years. While hospitalized they were assigned randomly to either placebo or chlorpromazine treatment. Many unmedicated-while-in-hospital patients showed greater long-term improvement, less pathology at follow-up, fewer rehospitalizations and better overall function in the community than patients who were given chlorpromazine while in the hospital. Factors related to post-hospital outcome were good premorbid history and short-lived paranoid characteristics. Considerations which may have an effect on the successful management of acute schizophrenic patients not on medication are mentioned. The findings underline the need for further study of how to utilize antipsychotic medication more selectively in the treatment of schizophrenia. Prevention of relapse is a major goal of maintenance treatment in patients with psychotic disorders. We performed a long-term comparison of a newer, atypical antipsychotic drug, risperidone, and an older, conventional neuroleptic drug, haloperidol, in terms of the rate of relapse in patients with schizophrenia and schizoaffective disorder.
                In a double-blind, prospective study at 40 sites, we randomly assigned adult outpatients in stable condition with chronic schizophrenia or schizoaffective disorder to receive treatment with flexible doses of either risperidone or haloperidol for a minimum of one year.
                Of the 397 patients who underwent randomization, data from 2 were excluded because they did not receive study medication; data from all 30 patients from one site were excluded by the sponsor, the Janssen Research Foundation, because of concern about the integrity of the data. The median duration of treatment was 364 days in the risperidone group and 238 days in the haloperidol group (P=0.02). Of the 177 patients assigned to risperidone and the 188 assigned to haloperidol who remained in the analysis, 44.1 percent and 52.7 percent, respectively, discontinued treatment for reasons other than relapse. The Kaplan-Meier estimate of the risk of relapse at the end of the study was 34 percent for the risperidone group and 60 percent for the haloperidol group (P<0.001); the risk ratio for relapse with haloperidol, from the Cox model, was 1.93 (95 percent confidence interval, 1.33 to 2.80; P<0.001). Early discontinuation of treatment for any reason was more frequent among haloperidol-treated patients (risk ratio, 1.52; 95 percent confidence interval, 1.18 to 1.96). Patients in the risperidone group had greater reductions in the mean severity of both psychotic symptoms and extrapyramidal side effects than those in the haloperidol group.
                Adult outpatients with clinically stable schizophrenia or schizoaffective disorder have a lower risk of relapse if they are treated with risperidone than if they are treated with haloperidol. A clinical study of 67 female schizophrenics was conducted. Thirty two patients of them treated with the Shuizhi (leech)-Dahuang (rhubarb) mixture mainly with low dosage of antipsychotic drugs (combined therapy group), while other 35 cases were treated with antipsychotic drugs only (control group). The result showed that their overall therapeutic effects were similar and the combined therapy group could reduce the dosages of antipsychotic drugs and its side effects, and tended to normalize the hemorheologic indices. Clozapine, a relatively expensive antipsychotic drug, is widely used to treat patients with refractory schizophrenia. It has a low incidence of extrapyramidal side effects but may cause agranulocytosis. There have been no long-term assessments of its effect on symptoms, social functioning, and the use and cost of health care.
                We conducted a randomized, one-year, double-blind comparative study of clozapine (in 205 patients) and haloperidol (in 218 patients) at 15 Veterans Affairs medical centers. All participants had refractory schizophrenia and had been hospitalized for the disease for 30 to 364 days in the previous year. All patients received case-management and social-rehabilitation services, as clinically indicated.
                In the clozapine group, 117 patients (57 percent) continued their assigned treatment for the entire year, as compared with 61 (28 percent) of the patients in the haloperidol group (P<0.001). As judged according to the Positive and Negative Syndrome Scale of Schizophrenia, patients in the clozapine group had 5.4 percent lower symptom levels than those in the haloperidol group at all follow-up evaluations (mean score, 79.1 vs. 83.6; P=0.02). The differences on a quality-of-life scale were not significant in the intention-to-treat analysis, but they were significant among patients who did not cross over to the other treatment (P=0.003). Over a one-year period, patients assigned to clozapine had fewer mean days of hospitalization for psychiatric reasons than patients assigned to haloperidol (143.8 vs. 168.1 days, P=0.03) and used more outpatient services (133.6 vs. 97.9 units of service, P=0.03). The total per capita costs to society were high -- $58,151 in the clozapine group and $60,885 in the haloperidol group (P=0.41). The per capita costs of antipsychotic drugs were $3,199 in the clozapine group and $367 in the haloperidol group (P<0.001). Patients assigned to clozapine had less tardive dyskinesia and fewer extrapyramidal side effects. Agranulocytosis developed in three patients in the clozapine group; all recovered fully.
                For patients with refractory schizophrenia and high levels of hospital use, clozapine was somewhat more effective than haloperidol and had fewer side effects and similar overall costs. This international, multicenter double-blind trial was designed to compare the therapeutic profile of an atypical antipsychotic, olanzapine, with that of a conventional dopamine D2 antagonist, haloperidol.
                A total of 1,996 patients at 174 sites in Europe and North America were randomly assigned to treatment with olanzapine (N = 1,336) or haloperidol (N = 660) over 6 weeks. The primary efficacy analysis involved the mean change from baseline to endpoint in total scores on the Brief Psychiatric Rating Scale (BPRS). Secondary analyses included comparisons of the mean change in positive and negative symptoms, comorbid depression, extrapyramidal symptoms, and overall drug safety.
                Olanzapine demonstrated clinical results superior to those of haloperidol on overall improvement according to the BPRS and on every secondary measure, including depression. Olanzapine was also associated with significantly fewer discontinuations of treatment due to lack of drug efficacy or adverse events. Substantially more olanzapine-treated patients (66.5%) than haloperidol-treated patients (46.8%) completed 6 weeks of therapy. Statistically significant advantages of olanzapine treatment were related to 1) change in negative symptoms, 2) extrapyramidal symptom profile, 3) effect on prolactin levels, and 4) response rate.
                Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenic psychopathology, with a substantially more favorable safety profile, than haloperidol. It meets several of the criteria for a novel atypical antipsychotic agent. Obesity and diabetes have caused problems for individuals with schizophrenia long before atypical antipsychotic agents. The prevalence of obesity, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia, and the Metabolic Syndrome has increased in people with schizophrenia as compared to the general population. Risk reduction studies for persons with obesity, diabetes, and cardiovascular disease indicate that cognitive/behavioral interventions that promote motivation and provide strategies to overcome the barriers in adherence to diet and activity modification are effective interventions for weight management and risk reduction. In the landmark multi-center randomized-controlled trial study, the Diabetes Prevention Project (DPP), a cognitive/behavioral intervention, was more successful in producing weight loss and preventing diabetes than the drugs metformin, troglitazone or placebo. This pilot study examined the effectiveness of a cognitive/behavioral group intervention, modified after the DPP program, in individuals with schizophrenia or schizoaffective disorder taking atypical antipsychotics in a large urban public mental health system. Outcome measures included body weight, body mass index, waist-hip ratios, and fasting glucose levels. Both groups demonstrated elevated fasting glucose levels and were obese with a mean BMI of 33. The group that received the cognitive/behavioral group intervention lost more weight than the treatment as usual group. The CB group participants lost an average of 5.4 lb or 2.9% of body weight, and those in the control group lost 1.3 lb or 0.6% body weight. The range of weight loss for the treatment group was from 1 to 20 lb. This pilot study has demonstrated that weight loss is possible with cognitive/behavioral interventions in a population with a psychotic disorder. nan This study presents a meta-analysis of the influence of several potentially biasing factors (eg industry support, extrapyramidal side effects) on efficacy of studies comparing second-generation antipsychotic (SGA) with first-generation antipsychotic (FGA) medications. We used the dataset from our previously published meta-analysis of 124 randomized controlled trials (RCTs) comparing SGAs with FGAs, to evaluate whether certain possible biases could influence the actual outcome on the total score of the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scores. Industry sponsorship was determined by contact with authors or publication statement. We calculated whether (1) industry sponsorship, (2) study quality, (3) extrapyramidal symptoms (EPS) properties, or (4) prophylactic antiparkinsonian medications influenced SGA vs FGA efficacy for each drug and averaged overall by two Hedges and Olkin-based meta-analyses. The analysis found that none of the factors was significantly associated with a particular outcome. While industry-sponsored articles may conclude their medication to be more favorable than that of a competitor in an RCT, we found that the observed efficacy was not influenced by sponsorship. Many attribute the finding that SGAs appears to be more efficacious than FGAs to be a result of EPS-decreasing efficacy (or its measurement). We were unable to confirm that the drug's EPS properties or antiparkinsonian management altered actual efficacy. Therapeutic intervention at the earliest phase of symptom exacerbation in schizophrenia is an important clinical need, but specific pharmacotherapeutic interventions for this phase of illness have not been established. This study examined diazepam efficacy for this phase of treatment.
                A double-blind, randomized clinical trial with 53 schizophrenic patients compared diazepam with placebo (with fluphenazine treatment for a comparison group). Treatment was initiated at the earliest signs of exacerbation, and symptom progression was the dependent measure used to evaluate efficacy.
                Diazepam was statistically superior to placebo in preventing symptom progression and was comparable to fluphenazine.
                Efficacy data support the use of diazepam in treating prodromal and early warning signs of symptom exacerbation in schizophrenia. This therapeutic strategy may be especially important for patients who refuse antipsychotic drugs or as a supplemental approach in a treatment plan that emphasizes low-dose antipsychotic therapy. The clinical effects of chlorpromazine (CPZ) administered in accordance with a double-blind design in one of three doses (200, 400 or 600 mg) were examined in 44 psychotic patients. The relationships between the effects and the CPZ concentrations in plasma and cerebrospinal fluid (CSF) were analyzed. The antipsychotic and side effects were rated according to the CPRS and the Simpson and Angus scale. CPZ concentrations were measured by a mass fragmentographic method. Treatment with CPZ resulted in a significant reduction of morbidity scores, without any clear dose relation. The final outcome was more favourable in women than in men. Extrapyramidal side effects but not somnolence were positively dose related. The antipsychotic effects tended to be positively related to the dose of CPZ in mg/kg as well as the CPZ concentrations in plasma and CSF. The greatest number of significant correlations between the CPZ concentration in CSF and the morbidity scores were seen after 2 weeks of treatment. The results indicated marked clinical improvement with CPZ concentrations above 1 ng/ml in CSF and 40 ng/ml in plasma. After 4 weeks of treatment the correlations between the CPZ concentrations and the clinical improvement were still positive but the coefficients were lower than at 2 weeks and only occasionaly significant. Extrapyramidal symptoms were significantly related to the CPZ concentrations in plasma and CSF. Somnolence was significantly related to the CPZ concentrations in CSF. Typical antipsychotic drugs frequently cause hyperprolactinemia and even galactorrhea. In addition, these side effects may result in noncompliance with antipsychotic treatment. Capacity to avoid hyperprolactinemia has been accepted as one atypical criterion. The aim of the present study was to compare effects of haloperidol, the most commonly used antipsychotic, and quetiapine, a novel antipsychotic agent used in Turkey, on serum prolactin (PRL) levels.
                The study consisted of 35 females diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 4(th) ed. (DSM-IV). Thirty-five patients in a drug-free period for at least 2 weeks were included to randomized quetiapine (n = 18) and haloperidol (n = 17) treatment group. All patients were assessed by Brief psychiatric rating scale (BPRS), Positive and negative syndrome scale (PANSS), and Extrapyramidal symptoms rating scale (ESRS). PRL levels were measured both at the beginning and at the sixth week of the study.
                Both treatment groups exhibited significant improvements in clinical signs as evaluated by BPRS and PANSS. While there was no significant difference in PRL level between groups at the beginning of the study, control prolactin (PRL) levels were significantly lower in quetiapine compared to haloperidol group. While no quetiapine group patients exhibited galactorrhea, we observed that two patients from the haloperidol group had galactorrhea related to hyperprolactinemia.
                The present study revealed that quetiapine is not associated with increase in PRL secretion in contrast to the conventional antipsychotic haloperidol. To investigate if ethyl-eicosapentaenoic acid (E-EPA) augmentation improves antipsychotic efficacy and tolerability in first-episode psychosis (FEP).
                We performed a 12-week, randomized, double-blind, placebo-controlled trial of 2-g E-EPA augmentation in 80 FEP patients. Sixty-nine patients were eligible for analysis; a post hoc analysis was computed for a subgroup of nonaffective FEP patients (N = 53). The first participant was included in November 2000 and the last participant completed the trial in August 2003. Primary outcome measures were symptom change scores and time to first response, while tolerability measures and cumulative antipsychotic dose were secondary outcome measures.
                Analysis of covariance controlling for baseline symptoms found no significant mean difference between E-EPA and placebo at week 12 for symptom change scores. Cox regression analysis revealed a significant treatment by diagnosis interaction (p = .024) for time to first response favoring E-EPA in nonaffective psychosis. Post hoc analysis for cumulative response rates further confirmed a higher response rate at week 6 (42.9% [15/35] vs. 17.6% [6/34] for all participants, p = .036; 54.2% [13/24] vs. 17.2% [5/29] for the nonaffective psychosis subset, p = .008); however, the difference at week 12 was no longer significant. Analysis of secondary outcome measures revealed that E-EPA-augmented participants needed 20% less antipsychotic medication between weeks 4 through 6 (p = .03), had less extrapyramidal side effects in the initial 9 weeks (p < .05 for all participants and for all timepoints), and reported less constipation (p = .011) and fewer sexual side effects (p = .016) than those treated with antipsychotic medication alone.
                The findings suggest that E-EPA may accelerate treatment response and improve the tolerability of antipsychotic medications. However, it was not possible to demonstrate a sustained symptomatic benefit of E-EPA in early psychosis, possibly due to a ceiling effect, since a high proportion of first-episode patients already achieve symptomatic remission with antipsychotic medication alone. Further controlled trials in nonaffective early psychosis seem warranted.
                Australian Clinical Trials Registry identifier 12605000267651 (http://actr.org.au). To compare the efficacy of two atypical antipsychotic drugs, olanzapine and risperidone, in schizophrenic patients with post-psychotic depression.
                A clinically significant decrease of MADRS scores occurred in patients treated with both drugs for 8 weeks.
                Atypical antipsychotic drugs may be particularly appropriate when treating schizophrenic patients with depression. The present study evaluated the effectiveness and safety of clozapine versus "high-dose" olanzapine in treatment-refractory adolescents with schizophrenia.
                Children, ages 10-18 years, who met DSM-IV criteria for schizophrenia and who were resistant or intolerant to at least two antipsychotic drugs were randomized to receive 12 weeks of double-blind flexibly dosed treatment with clozapine (n = 18) or "high-dose" olanzapine (up to 30 mg/day) (n = 21). The primary efficacy measure was response (improvement), defined as a decrease of 30% or more in total Brief Psychiatric Rating Scale score from baseline and a Clinical Global Impression Scale improvement rating of "1" (very much improved) or "2" (much improved).
                Significantly more clozapine-treated adolescents met response criteria (66%) compared with olanzapine-treated subjects (33%). Clozapine was superior to olanzapine in terms of reduction of the psychosis cluster scores and negative symptoms from baseline to end point. However, both treatments were associated with significant weight-gain and related metabolic abnormalities.
                This double-blind randomized comparison of two second-generation antipsychotic drugs for treatment-refractory adolescents with schizophrenia supports clozapine as the agent of choice. The development of interventions to limit weight gain and metabolic side effects are needed to enhance the risk-benefit profile for both study treatments. Although psychoactive medications have substantial side effects in the elderly, these drugs are used frequently in nursing homes. Few interventions have succeeded in changing this situation, and little is known about the clinical effects of such interventions.
                We studied six matched pairs of nursing homes; at one randomly selected nursing home in each pair, physicians, nurses, and aides participated in an educational program in geriatric psychopharmacology. At base line we determined the type and quantity of drugs received by all residents (n = 823), and a blinded observer performed standardized clinical assessments of the residents who were taking psychoactive medications. After the five-month program, drug use and patient status were reassessed.
                Scores on an index of psychoactive-drug use, measuring both the magnitude and the probable inappropriateness of medication use, declined significantly more in the nursing homes in which the program was carried out (experimental nursing homes) than in the control nursing homes (decrease, 27 percent vs. 8 percent; P = 0.02). The use of antipsychotic drugs was discontinued in more residents in the experimental nursing homes than in the control nursing homes (32 percent vs. 14 percent); the comparable figures for the discontinuation of long-acting benzodiazepines were 20 percent vs. 9 percent, and for antihistamine hypnotics, 45 percent vs. 21 percent. In the experimental nursing homes residents who were initially taking antipsychotic drugs showed less deterioration on several measures of cognitive function than similar residents in the control facilities, but they were more likely to report depression. Those who were initially taking benzodiazepines or antihistamine hypnotic agents reported less anxiety than controls but had more loss of memory. Most other measures of clinical status remained unchanged in both groups.
                An educational program targeted to physicians, nurses, and aides can reduce the use of psychoactive drugs in nursing homes without adversely affecting the overall behavior and level of functioning of the residents. This study compared the therapeutic efficacy of thioridazine, loxapine, and a placebo in the treatment of behavioral disturbances in nursing home patients with dementia. Antipsychotic medications were effective for the specific behavioral problems of anxiety, excitement, emotional lability, and uncooperativeness. Subjects with the most severe symptoms at baseline assessment derived the greatest benefit from treatment. Sedation, extrapyramidal symptoms, and decreased blood pressure were common side effects among patients treated with the antipsychotic drugs. The authors conclude that antipsychotic medication has a definite but limited therapeutic role in the treatment of behavioral disturbances in nursing home patients with dementia. The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder.
                In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period).
                Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain.
                The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small. This 12-week, double-blind study evaluated the effectiveness of risperidone (4 mg/day), quetiapine (400 mg/day), or fluphenazine (12.5 mg/day) in a stringently defined treatment-resistant population of people with schizophrenia. No differences were noted in total Brief Psychiatric Rating Scale (BPRS) or Clinical Global Impression scores among the drug groups (n = 38). More subjects tended to complete the study on risperidone (69%) or quetiapine (58%) than those treated with fluphenazine (31%; P value not significant). Eighty-nine percent of those who discontinued on fluphenazine (8 of 9) were due to lack of efficacy. Discontinuation due to adverse effects was low, with only 2 subjects (both on quetiapine) stopping due to side effects. Three of 13 risperidone-treated subjects (23%) and 3 of 12 quetiapine-treated subjects (25%) met response criteria (decrease of 20% of total BPRS score), whereas 2 of 13 subjects (15%) responded to fluphenazine. Side effect occurrence was similar among drug groups and EPS ratings on the Simpson Angus Scale improved in all drug groups (quetiapine, 1.64; risperidone, 1.30; fluphenazine, 0.69; P value not significant). Despite the newer class of second-generation antipsychotic medications, this treatment-resistant population remains difficult to treat. Many people have only minimal to modest improvements with antipsychotic treatment and most continue to have residual psychotic symptoms. Treatment with first- and second-generation antipsychotics may demonstrate similar efficacy; however, patients treated with second-generation antipsychotics may be more likely to adhere to treatment. Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment.
                To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious.
                Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up.
                National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge.
                Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics.
                After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n = 12) or olanzapine (n = 13).
                The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms.
                Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P = .04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n = 6) and seizures (n = 1).
                While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events. Penfluridol is a diphenylbutylpiperdine derivative with a half-life of sixty-six (66) hours. The present study was designed to determine its efficacy for the maintenance of schizophrenia. In a 52 week double-blind study, once weekly doses of penfluridol were compared with once daily doses of chlorpromazine in 56 schizophrenic patients receiving maintenance treatment on an outpatient basis. Both drugs were similar in their clinical effectiveness; no major side effects occurred with either drug. Schizophrenic patients have high rates of cigarette smoking compared with the general population. We compared sustained-release (SR) bupropion with placebo for smoking cessation in patients with schizophrenic disorders. We also examined how antipsychotic class predicts smoking cessation outcomes with bupropion.
                Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were randomized to bupropion SR (BUP, 300 mg/day) or placebo (PLA). Outcomes included treatment retention, smoking abstinence rates, expired breath carbon monoxide (CO) levels, psychotic symptoms, and medication side effects.
                Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [BUP, 8/16 (50.0%), PLA, 2/16 (12.5%); chi(2) = 5.24, df = 1, p <.05], and reduced CO levels during the trial [Medication x Time interaction; Z = 3.09, p <.01]. Positive schizophrenia symptoms were not altered by BUP, but negative symptoms were significantly reduced. Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP. Major side effects were dry mouth, gastrointestinal symptoms, headache, and insomnia.
                Our results suggest that 1) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers; 2) BUP is well-tolerated and safe for use in these patients; and 3) atypical antipsychotics may enhance smoking cessation outcomes with BUP. Fifteen schizophrenic inpatients were treated in a double-blind comparison study of clozapine versus chlorpromazine. Clozapine appeared to be at least as effective as chlorpromazine without producing any extrapyramidal reactions. Although bone marrow toxicity associated with clozapine has led to the drug's withdrawal from clinical use, data from studies of clozapine demonstrate that a drug can be effective antipsychotic without producing neurologic reactions. The objective of the study was to examine whether patients with schizophrenia who were judged to be stable on long-term treatment with conventional antipsychotic medications would further benefit from a switch to an atypical antipsychotic drug. Thirty-six subjects with schizophrenia spectrum disorder, on conventional antipsychotic medication therapy for at least 2 years, were randomized in double-blind fashion to risperidone versus olanzapine. Patients were titrated up to 6 mg risperidone or 15 mg olanzapine as tolerated, followed by tapering and discontinuation of conventional antipsychotic medication. Atypical antipsychotic agents were then administered alone (monotherapy) for 12 weeks. Efficacy and tolerability were assessed using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, and Simpson Angus Scale. Body weight was measured at each visit. Both treatment groups exhibited marked and similar improvement in the total PANSS score from baseline to study endpoint (22 weeks) [risperidone: baseline=59.3 (SE 3.1), 22 weeks=44.3 (SE 2.3) (p<0.001); olanzapine: baseline=55.9 (SE 3.3), 22 weeks=46.9 (SE 3.2) (p<0.001). Both groups also exhibited significant reductions in PANSS factor scores for positive and negative symptoms and disorganized thoughts. Only risperidone-treated patients exhibited significant decreases in uncontrolled hostility/excitement and anxiety and depression. Of note, while positive factor scores exhibited the majority of change within the first 10 weeks, negative factor scores continued to decline significantly in both treatment groups throughout the study. Tolerability assessments did not differ between groups. The results indicate that both atypical antipsychotic medications provided significant additional improvement in symptom severity in patients with schizophrenia previously on conventional antipsychotic agents. Evidence that the metabolism of phospholipids and polyunsaturated fatty acids (PUFA) is abnormal in schizophrenia provided the rationale for intervention studies using PUFA supplementation. An initial open label study indicating efficacy for n-3 PUFA in schizophrenia led to two small double-blind pilot studies. The first study was designed to distinguish between the possible effects of two different n-3 PUFA: eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA). Forty-five schizophrenic patients on stable antipsychotic medication who were still symptomatic were treated with either EPA, DHA or placebo for 3 months. Improvement on EPA measured by the Positive and Negative Syndrome Scale (PANSS) was statistically superior to both DHA and placebo using changes in percentage scores on the total PANSS. EPA was significantly superior to DHA for positive symptoms using ANOVA for repeated measures. In the second placebo-controlled study, EPA was used as a sole treatment, though the use of antipsychotic drugs was still permitted if this was clinically imperative. By the end of the study, all 12 patients on placebo, but only eight out of 14 patients on EPA, were taking antipsychotic drugs. Despite this, patients taking EPA had significantly lower scores on the PANSS rating scale by the end of the study. It is concluded that EPA may represent a new treatment approach to schizophrenia, and this requires investigation by large-scale placebo-controlled trials. Weight gain is a common adverse effect associated with the use of most antipsychotic drugs. Leptin has been reported to be associated with antipsychotic-induced weight gain. Previous studies have demonstrated a relationship between the atypical antipsychotics clozapine and olanzapine and serum leptin levels. We planned to comparatively investigate the effects of the atypical antipsychotics quetiapine, olanzapine, risperidone, and clozapine on leptin and triglyceride levels and weight gain.
                The study population comprised 56 patients with DSM-IV schizophrenia, who were divided into 4 treatment groups: quetiapine (N = 14), olanzapine (N = 14), risperidone (N = 14), or clozapine (N = 14) monotherapy, and a control group of 11 patients receiving no psychopharmacologic treatment. The patients were evaluated at baseline and at the sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, and fasting serum leptin and triglyceride levels. Data were gathered in 2001 and 2002.
                Olanzapine and clozapine caused a marked increase in weight and serum triglyceride and leptin levels, though increases in these variables were modest in the patients receiving quetiapine and minimal in those receiving risperidone. There were positive correlations between serum leptin levels and BMI and triglyceride levels. Clinical efficacy, as indicated by decrease in total PANSS scores, was associated with leptin levels in all atypical antipsychotic groups.
                Our results suggest that leptin may be associated with olanzapine- and clozapine-induced weight gain and that quetiapine appears to have modest influence and risperidone appears to have minimal influence on leptin and triglyceride levels and weight gain compared with olanzapine and clozapine. Although there is a consensus that clozapine is more effective than conventional antipsychotic drugs for treatment-resistant schizophrenia, there is great heterogeneity among results of relevant trials.
                To re-evaluate the evidence comparing clozapine with conventional antipsychotics and to investigate sources of heterogeneity.
                Individual studies were inspected with assessment of clinical relevance of results. Meta-regression analysis was performed to investigate sources of heterogeneity.
                Ten trials were examined. Recent large-scale studies have not found a substantial advantage for clozapine, especially in terms of a clinically relevant effect. Meta-regression showed that shorter study duration, financial support from a drug company and higher baseline symptom score consistently predicted greater advantage of clozapine.
                It may be inappropriate to combine studies in meta-analysis, given the degree of heterogeneity between their findings. The benefits of clozapine compared with conventional treatment may not be substantial. Atypical antipsychotics offer advantages over earlier drugs for the treatment of schizophrenia, although few data exist on the relative merits of different atypical antipsychotics. A multicentre, double-blind, randomized trial was performed to compare amisulpride and olanzapine in the treatment of acute schizophrenia. Adult schizophrenic patients with dominant positive symptomatology received amisulpride (200-800 mg/day) or olanzapine (5-20 mg/day) for 6 months. The primary efficacy variable was change from baseline of the Brief Psychiatric Rating Scale (BPRS) score, assessed with a non-inferiority analysis. The evolution of positive and negative symptomatology, depression, social functioning and quality of life were assessed. Safety evaluation included adverse event reporting, neurological status and body weight. The improvement of BPRS score was 32.7% in the amisulpride group and 33.0% in the olanzapine group; thus, the efficacy of amisulpride was not inferior to that of olanzapine. All other secondary efficacy outcome variables evolved to a similar extent in both groups. Adverse event frequency was similar in both groups. Amenorrhoea was encountered only in the amisulpride group (6.2% of patients), whereas elevations of liver transaminases were more frequent in the olanzapine group (17% versus 3.7% of patients). The incidence and mean extent of clinically relevant weight gain were higher in the olanzapine group (35.1% and 3.9 kg) than in the amisulpride group (20.6% and 1.6 kg). The efficacy of amisulpride is not inferior to that of olanzapine in the treatment of acute schizophrenia. The side-effect profile of the two drugs differed. Today's treatment of acute psychosis usually includes short-term hospitalization and anti-psychotic drug treatment. The Soteria project compared this form of treatment (control) with that of a small, home-like social environment, usually without neuroleptics (experimental).
                Newly diagnosed, young, unmarried persons with DSM-II schizophrenia were randomly assigned to treatment in two experimental and two control settings. Subjects and families were assessed at admission on 29 independent variables. Treatment environments were studied by means of Moos', COPES or WAS scales. Three dependent six week psychopathology outcome measures were collected.
                The groups were comparable on 25 of 29 admission variables. The environments of the two experimental and two control settings were different from each other. The milieus were similar to each other within each condition. At six weeks, psychopathology in both groups had improved significantly, and similarly, and overall change was the same.
                Specially designed, replicable milieus were able to reduce acute psychotic symptomatology within six weeks, usually without antipsychotic drugs, as effectively as usual hospital ward treatment that included routine neuroleptic drug use. To evaluate a novel approach to the prophylaxis of schizophrenic relapse characterised by administration of brief courses of neuroleptic for the earliest non-psychotic signs of relapse (prodromal symptoms).
                Two year follow up of subjects randomised, double blind, to receive either active (control group) or placebo (intermittent group) depot neuroleptic medication. Both groups received brief courses of oral neuroleptic when prodromal symptoms or relapse occurred.
                Psychiatric outpatient department, Charing Cross Hospital, London.
                54 Stable patients in remission who met the American Psychiatric Association's DSM-III criteria for schizophrenia on the basis of case notes.
                Survival without relapse, survival without hospitalisation, point prevalence of extrapyramidal side effects and tardive dyskinesia, structured assessment of social functioning (social adjustment scale II), and frequency of prodromal symptoms.
                Of 19 relapses recorded over two years, 10 (53%) were preceded by non-psychotic prodromal signs. Survival rates for both relapse and hospitalisation were worse with intermittent treatment than continuous treatment over the two year follow up: 92% of controls and only 54% of patients given intermittent treatment survived the two year period without hospitalisation. Prolonged or frequent relapses as well as episodes of prodromal symptoms were more frequent with intermittent treatment. Lower scores for extrapyramidal side effects were recorded in the intermittent treatment group, but periodic assessments of social functioning failed to show any social advantages from this.
                The findings are at variance with a previous report of one year follow up in this cohort and attest to the superiority of continuous depot neuroleptic prophylaxis in preventing both psychotic and neurotic or dysphoric morbidity in schizophrenia. Thirty-two schizophrenic patients, previously treated with antipsychotics, were treated with haloperidol decanoate and flupenthixol decanoate in a double-blind cross-over study. The drugs were given for 24 weeks each at an individually adapted dose. The last three injections of either drug were given at fixed 4-week intervals. The mean dose over the two treatment periods changed from 131 mg (start) to 151 mg (week 24) in the haloperidol decanoate group and from 56 mg to 66 mg in the flupenthixol decanoate group, the inter-drug ratio being 2.3:1. During the first study period, the patients' condition remained rather stable with both drugs. After crossing-over, the symptoms were further reduced with haloperidol decanoate but increased with flupenthixol decanoate. Side effects of the two drugs were comparable and were generally few and mild. It was concluded that 4-week intramuscular administration of haloperidol decanoate provides appropriate control of schizophrenic symptoms, but that flupenthixol decanoate should be dosed at shorter intervals. Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone.
                Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months.
                The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023).
                Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy. This double-blind placebo controlled, parallel design clinical trial compared the therapeutic effects of the addition of lithium or placebo to haloperidol in 21 seriously ill state hospital patients with DSM-III-R schizophrenia, who did not have concurrent affective disorders and who had not responded to previous trials of conventional antipsychotic medication. During a baseline period of 6 weeks, patients were switched to a stable dose of haloperidol (mean +/- SD dose = 13.6 +/- 8.1 mg/day). Patients were then randomized to receive either lithium or placebo in addition to haloperidol for 8 weeks (mean +/- SD lithium level = 0.98 +/- 0.13 mEq/l). Symptoms and side effects were assessed weekly. Improvement in symptoms correlated with the non-blind adjustment of antipsychotic dose, but not with lithium or placebo treatment. Side effects ratings did not differ between the two groups, but one patient developed a reversible delirium associated with combined lithium/haloperidol treatment. For these long-term, severely ill patients, combined treatment afforded no advantage over treatment with haloperidol alone. While the usefulness of atypical antipsychotics for improving cognitive function has been proven, the specific effects of these drugs are still unknown. The objective of this study was to investigate changes of the immediate memory and verbal working memory in patients with chronic schizophrenia after switching to one of four atypical antipsychotic agents and cessation of anticholinergic therapy. The subjects included 77 schizophrenic patients who were treated primarily with typical antipsychotics. Treatment was randomly switched to one of four atypical antipsychotics (olanzapine, perospirone, quetiapine, or risperidone) over a 4-week period, and then the drug was continued for another 4 weeks while the patient was taken off anticholinergics. The immediate memory, verbal working memory, and symptoms were evaluated. Significant improvement of immediate memory was only seen with olanzapine and risperidone. Improvement was also seen after switching to perospirone, but immediate memory worsened after treatment with this anticholinergic drug was discontinued. Deterioration was seen after switching to quetiapine, but immediate memory improved and reached the previous level after treatment with anticholinergic drugs was discontinued. Significant improvement of the verbal working memory was only seen during risperidone administration. The findings suggested that switching chronic schizophrenic patients to atypical antipsychotics can improve both the immediate memory and the verbal working memory when risperidone is used, while improvement of immediate memory can be expected with olanzapine. From the viewpoint of improving the memory, quetiapine should not be administered concomitantly with anticholinergic drugs, and caution should be exercised when discontinuing anticholinergic drugs during treatment with perospirone. The objective was to test effects of ethyl eicosapentaenoate (E-E) on persistent ongoing symptoms in patients receiving different types of anti-schizophrenic drugs, typical antipsychotics, new atypical antipsychotics, and clozapine. 115 patients with DSM-IV-defined schizophrenia were studied, 31 on clozapine, 48 on new atypical drugs and 36 on typical antipsychotics. Placebo or 1, 2 or 4 g/day of E-E was given for 12 weeks in addition to the background medication. The main assessment was change from baseline to 12 weeks on the PANSS and its sub-scales. There were no treatment-related side effects or adverse biochemical or haematological effects. Patients on 2 and 4 g/day E-E showed significant reductions in triglyceride levels which had been elevated by clozapine. In patients given 2 g/day E-E there were improvements on the PANSS and its sub-scales, but there was also a large placebo effect in patients on typical and new atypical antipsychotics and no difference between active treatment and placebo. In patients on clozapine, in contrast, there was little placebo response, but a clinically important and statistically significant effect of E-E on all rating scales. This effect was greatest at 2 g/day. There was a positive relationship between improvement on rating scales and rise in red blood cell arachidonic acid concentration. A 6-week double-blind comparison of mianserin, a new antidepressant, and amitriptyline allowed us to explore the problem of demonstrating main effect differences in drug/drug trials when the focus is primarily only upon efficacy or upon common adverse symptomatology. Statistical analyses of standard psychiatric rating scales revealed no significant treatment differences, while both treatment groups exhibited significant parallel improvement across time. Examination of treatment emergent symptoms indicated that, while it evoked fewer anticholinergic symptoms than amitriptyline, mianserin exhibited a different profile of adverse symptomatology. The usefulness of a measure of the benefit/risk ratio was described as a means of clarifying drug/drug comparisons. To evaluate the long-term efficacy of a school-based approach to drug abuse prevention.
                Randomized trial involving 56 public schools that received the prevention program with annual provider training workshops and ongoing consultation, the prevention program with videotaped training and no consultation, or "treatment as usual" (ie, controls). Follow-up data were collected 6 years after baseline using school, telephone, and mailed surveys.
                A total of 3597 predominantly white, 12th-grade students who represented 60.41% of the initial seventh-grade sample.
                Consisted of 15 classes in seventh grade, 10 booster sessions in eighth grade, and five booster sessions in ninth grade, and taught general "life skills" and skills for resisting social influences to use drugs.
                Six tobacco, alcohol, and marijuana use self-report scales were recorded to create nine dichotomous drug use outcome variables and eight polydrug use variables.
                Significant reductions in both drug and polydrug use were found for the two groups that received the prevention program relative to controls. The strongest effects were produced for individuals who received a reasonably complete version of the intervention--there were up to 44% fewer drug users and 66% fewer polydrug (tobacco, alcohol, and marijuana) users.
                Drug abuse prevention programs conducted during junior high school can produce meaningful and durable reductions in tobacco, alcohol, and marijuana use if they (1) teach a combination of social resistance skills and general life skills, (2) are properly implemented, and (3) include at least 2 years of booster sessions. A six-year, school-based prevention program, which modified classroom teacher practices, offered parent training, and provided child social skills training, was evaluated for its effects on school failure, drug abuse, and delinquency among low-income urban children. Compared to a low-income control group, children in the intervention group showed enhanced school commitment and class participation. The girls in the group also evidenced lower rates of substance use initiation, while the boys exhibited increased social and school work skills. Children whose parents abuse drugs are exposed to numerous factors that increase the likelihood of future drug abuse. Despite this heightened risk, few experimental tests of prevention programs with this population have been reported. This article examines whether intensive family-focused interventions with methadone treated parents can reduce parents' drug use and prevent children's initiation of drug use.
                Parents were assigned randomly into intervention and control conditions and assessed at baseline, post-test, and 6 and 12 months following the intervention. Children were assessed at baseline, and 6- and 12-month follow-up points.
                Two methadone clinics in Seattle, Washington.
                One hundred and forty-four methadone-treated parents, and their children (n = 178) ranging in age from 3 to 14 years old.
                The experimental intervention supplemented methadone treatment with 33 sessions of family training combined with 9 months of home-based case management. Families in the control condition received no supplemental services.
                Parent measures included: relapse and problem-solving skills, self-report measures of family management practices, deviant peer networks, domestic conflict and drug use. Child measures included self-report measures of rules, family attachment, parental involvement, school attachment and misbehavior, negative peers, substance use and delinquency.
                One year after the family skills training, results indicate significant positive changes among parents, especially in the areas of parent skills, parent drug use, deviant peers and family management. Few changes were noted in children's behavior or attitudes.
                Programs such as this may be an important adjunct to treatment programs, helping to strengthen family bonding and to reduce parents' drug use.
The results clearly demonstrate the superiority of antipsychotic drugs compared to placebo in preventing relapse. This effect must be weighed against the side effects of antipsychotic drugs. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality associated with these drugs.