Sexual dysfunction in first-episode schizophrenia patients: results from European First Episode Schizophrenia Trial.

Sexual dysfunctions (SDs) occur frequently in schizophrenia patients and have a huge impact on quality of life and compliance. They are often associated with antipsychotic medication. Nicotine consumption, negative or depressive symptoms, and physical illness are also discussed as contributing factors. Data on SD in first-episode schizophrenia patients are scarce.As part of the European First Episode Schizophrenia Trial, first-episode schizophrenia patients were randomly assigned to 5 medication groups. We assessed SD by analyzing selected items from the Udvalg for Kliniske Undersugelser at baseline and at 5 following visits.Differences between antipsychotics were small for all SDs, and fairly little change in the prevalence of SDs was seen over the course of the study. A significantly larger increase of amenorrhea and galactorrhea was seen with amisulpride than with the other medications. In men, higher age, more pronounced Positive and Negative Syndrome Scale general psychopathology symptoms, and higher plasma prolactin levels predicted higher rates of erectile and ejaculatory dysfunctions. Positive and Negative Syndrome Scale negative symptoms and higher age were predictors for decreased libido.In women, higher prolactin plasma levels were identified as a predictor of amenorrhea. Positive and Negative Syndrome Scale negative symptoms predicted decreased libido.All evidence taken together underscores the influence of the disease schizophrenia itself on sexual functioning. In addition, there is a strong correlation between the prolactin-increasing properties of amisulpride and menstrual irregularities.

[Psycho-educational coping-oriented group therapy for schizophrenia patients]. / Psychoedukative und bewältigungsorientierte Gruppentherapie für SchizophreniepatientInnen.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of a psycho-educational, coping-oriented therapy programme for patients with schizophrenia or schizo-affective disorder. METHOD: Controlled, prospective study design. In the experimental group the Therapy Manual for Psycho-education and Coping with Illness (PKB) was used, providing targeted information on the illness, medical treatment, prodromal symptoms, and health behaviour. Controls participated in supportive dialogues or in an occupational rehabilitation programme. Psychopathology, re-hospitalisations, knowledge, functional outcome and coping strategies were assessed before, directly after and 12 months post therapy. RESULTS: 82 patients participated. In both groups (experimental, control) a significant improvement in psychopathology and general functioning level were observed. Specific advantages for patients of the experimental group were limited to a few aspects, including rehospitalizations in the first year and certain coping strategies. CONCLUSION: In the treatment of schizophrenia different forms of psycho-social intervention (experimental, control) can be effective. Identification of subgroups profiting specially from certain types of intervention should be subject of future research.

Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: a randomized, open-label clinical trial (EUFEST).

OBJECTIVE: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. METHODS: Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. RESULTS: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. CONCLUSION: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial.

BACKGROUND: Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. METHODS: We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. FINDINGS: The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. INTERPRETATION: This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.

Alterations of glucose metabolism during treatment with clozapine or amisulpride: results from a prospective 16-week study.

Although second-generation antipsychotics have notable benefits as compared to typical antipsychotics, their use has been associated with metabolic disturbances, such as alterations of glucose homeostasis. It is still being debated whether this is a class effect of second-generation antipsychotics. We conducted a prospective, open study comparing body weight, parameters of insulin resistance in schizophrenia patients treated with either clozapine (n = 10) or amisuLpride ( n = 12). All parameters were assessed monthly over a period of 12 to 16 weeks. Body mass index (BMI), fasting serum insulin levels and the Homeostasis Model Assessment (HOMA) index for insulin resistance increased significantly in patients treated with clozapine. None of these parameters increased significantly in patients treated with amisulpride. This study indicates that treatment with clozapine appears to have a higher risk to lead to metabolic disturbances than amisupride.

The use of amisulpride in the treatment of acute psychosis.

The management of acute episodes in schizophrenia is frequently initiated in the psychiatric emergency department and requires rapid intervention to relieve distress and psychiatric symptoms. Both non-pharmacological and pharmacological interventions are needed to calm the patient and prevent potential harm to the patient or others. Treatment is a step-by-step process including management of behavioral symptomatology, diagnosis of potential organic causes, and evaluation of potential substance abuse. Better care is delivered if predefined standard operating procedures are adopted systematically. The ultimate goal of treatment is to establish a therapeutic alliance with the patient. Atypical antipsychotics given orally are recommended as a first-line treatment. As the treatment endpoint is calmness rather than sleep, a non-sedative antipsychotic agent is usually preferred. Drug tolerance is a major issue for the patient. Amisulpride is an effective atypical antipsychotic agent in this context. The optimal dose is 800 mg/day, which is effective on positive and negative symptoms and can be given from the first day with a low risk of extrapyramidal symptoms. Since drug-drug interactions are limited, agitation and anxiety may be controlled by short-term adjunctive therapy with benzodiazepines. In conclusion, amisulpride is an appropriate first-line treatment for the management of acute psychosis.

Early changes of plasma lipids during treatment with atypical antipsychotics.

Metabolic side effects have been found earlier during treatment with second-generation antipsychotics. Among those disturbances serum lipids are less investigated. We conducted a prospective, open study in schizophrenia patients in order to compare body weight and serum lipids during treatment with amisulpride, ziprasidone, clozapine or olanzapine over a period of 4 weeks. Body mass index, total cholesterol and triglycerides increased in patients treated with clozapine and olanzapine whereas high-density lipoprotein cholesterol decreased in those patients. In patients treated with amisulpride or ziprasidone, we found a decrease in body mass index and total cholesterol whereas high-density lipoprotein cholesterol increased. Our results indicate that treatment with ziprasidone and amisulpride is more favourable than treatment with clozapine and olanzapine with respect to the risk to induce weight gain and hyperlipidaemia. These results are important with regard to the increased risk for cardiovascular complications in patients with schizophrenia.

Association between antipsychotic-induced elevation of liver enzymes and weight gain: a prospective study.

We conducted a prospective, open study in schizophrenia patients treated with second-generation antipsychotics in order to investigate the risk for elevation of liver enzymes and its correlation to antipsychotic-induced weight gain. Body mass index, serum transaminases, plasma serum levels of the antipsychotic used, and blood cell counts were measured weekly during the first 6 weeks of treatment and monthly thereafter. A considerable proportion of subjects showed an increase beyond normal levels of at least one of the measured transaminases. In all but one case, the elevation of liver enzymes was transient. We found a statistically significant correlation between weight gain and liver enzyme elevation. The group of patients that had gained at least 7% of the baseline body weight showed significantly higher increases of transaminases as compared with those who had gained less than 7% weight. We conclude that antipsychotic-induced elevation of liver enzymes is mostly transient and could be associated with weight gain.

Correlates of subjective and functional outcomes in outpatient clinic attendees with schizophrenia and schizoaffective disorder.

Outcome in schizophrenia is multidimensional and, thus, consists of clinical,humanitarian, rehabilitative and cost domains. Accordingly, recovery is conceptualized as the ability to function in the community, socially and vocationally, as well as being relatively free of disease-related psychopathology. The present cross-sectional study examined the relationship of premorbid functioning, psychopathology, insight, attitudes toward medication and side-effects, as well as sociodemographic factors with treatment outcomes in terms of quality of life (QOL) and psychosocial functioning among 60 regular attendees of a specialized schizophrenia outpatient clinic. Both insight into the illness as well as attitudes toward treatment indicated satisfactory compliance. Premorbid school and social functioning were positively correlated with actual employment status, and premorbid social functioning was further positively correlated with QOL and global functioning. Attitudes toward treatment were positively associated with global QOL, and with the patients' living situation. Both positive and negative symptoms as well as asthenia were negatively associated with QOL, while cognitive symptoms negatively influenced occupational functioning. Older patients lived independently and/or in a partnership more often, but had a lesser likelihood of competitive employment. Our observations suggest that subjective and functional outcomes in highly compliant patients are mainly predicted by psychopathological symptoms and unchangeable sociodemographic variables.

Dropout rates in placebo-controlled and active-control clinical trials of antipsychotic drugs: a meta-analysis.

CONTEXT: Dropout rates in randomized clinical trials of antipsychotic drugs have consistently been reported to be high, and the use of a placebo-controlled design is hypothesized to be one of the reasons for this. OBJECTIVE: To investigate this hypothesis in a meta-analysis of available data from pertinent clinical trials. DATA SOURCES: Comprehensive search of PubMed- and MEDLINE-listed journals. STUDY SELECTION: Double-blind randomized controlled clinical trials of the second-generation antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole meeting the following criteria: unselected patient population with a diagnosis of schizophrenia or schizoaffective disorder, change in psychopathologic symptoms as the primary end point, and trial duration of 12 weeks or less. DATA EXTRACTION: Sample size, mean age, baseline disease severity, dropout rate, trial design, trial duration, and publication year. DATA SYNTHESIS: Thirty-one trials meeting the inclusion criteria were found, comprising 10 058 subjects. Weighted mean dropout rates in the active treatment arms were significantly higher in placebo-controlled trials (PCTs) than in active-control trials: 48.1% (PCTs) vs 28.3% (active-control trials) for second-generation antipsychotics (odds ratio, 2.34; 95% confidence interval, 1.58-3.47) and 55.4% (PCTs) vs 37.2% (active-control trials) for classical antipsychotics (odds ratio, 2.10; 95% confidence interval, 1.29-3.40). Within PCTs, attrition rates were significantly higher in the placebo arms than with second-generation antipsychotics (60.2% vs 48.1%; odds ratio, 1.63; 95% confidence interval, 1.37-1.94). Within the subset of trials in which both second-generation and classical antipsychotics were used, dropout rates were significantly higher with classical antipsychotics. CONCLUSIONS: Use of a placebo-controlled design had a major effect on the dropout rates observed. Because high dropout rates affect the generalizability of such studies, it is suggested that, in addition to the PCTs, studies with alternative designs need to be considered when evaluating an antipsychotic's clinical profile.

Patient outcomes in schizophrenia I: correlates with sociodemographic variables, psychopathology, and side effects.

OBJECTIVE: The present cross-sectional study examined the relationships of psychopathology, side effects, and sociodemographic factors with treatment outcomes in terms of patients' quality of life (QOL), functioning, and needs for care. METHOD: Sixty outpatients with chronic schizophrenia who had been treated with either clozapine or olanzapine for at least 6 months were investigated. RESULTS: Most psychopathological symptoms as well as psychic side effects, weight gain, and female sex were associated with lower QOL, while cognitive symptoms correlated with better QOL. Female sex, cognitive symptoms, and parkinsonism negatively influenced occupational functioning, and negative symptoms determined a lesser likelihood of living independently. Age, education, depression/anxiety, negative symptoms, and psychic side effects were predictors of patients' needs for care. CONCLUSION: Our results highlight the complex nature of patient outcomes in schizophrenia. They reemphasize the need of targeting effectiveness, i.e. both symptomatic improvement as well as drug safety, in such patients.

Patient outcomes in schizophrenia II: the impact of cognition.

BACKGROUND: Cognitive dysfunction is increasingly considered to be the strongest clinical predictor of poor long-term outcome in schizophrenia. Associations have been found between the severity of cognitive deficits and social dysfunction, impairments in independent living, occupational limitations, and disturbances in quality of life (QOL). METHODS: In this cross-sectional study, the relationships of cognitive deficits and treatment outcomes in terms of QOL, needs, and psychosocial functioning were examined in 60 outpatients with schizophrenia who had a duration of illness over 2 years and had been treated with either clozapine or olanzapine for at least 6 months. RESULTS: The present study suggests that cognitive functioning might be a predictor of work functioning/independent living outcome in stabilized patients with schizophrenia: deficits of visual memory and working memory were negatively associated with occupational functioning, and older patients lived independently and/or in a stable partnership more often. The patients' assessments of QOL and needs for care did not show any significant associations with cognitive functioning. DISCUSSION: These findings suggest that cognitive functioning is a key determinant of work functioning/independent living for stable outpatients with schizophrenia.

QTc variability in schizophrenia patients treated with antipsychotics and healthy controls.

QTc prolongation is associated with the administration of some antipsychotics but the QTc interval is also known to vary physiologically. There is little published evidence about changes in QTc variability during treatment with antipsychotics. In this prospective investigation, we analyzed ECGs in 61 patients suffering from a schizophrenic disorder who were treated with different antipsychotics and 31 sex- and age-matched healthy controls. We found no differences in QTc intervals nor in QTc variability between patients and controls. Our results raise the question of the clinical relevance of a single ECG for diagnostics of cardiac complications in schizophrenia patients and suggest the need to conduct ECG monitoring in patients at high risk for cardiac complications during antipsychotic treatment.

Switching between second-generation antipsychotics: why and how?

The introduction of second-generation antipsychotics represents an important advance in the treatment of schizophrenia. Although these drugs are generally very effective, not all patients respond in the same way. Partial response with persistent positive and negative symptoms and residual symptoms may force physicians to change antipsychotic medication. As more and more second-generation antipsychotics are introduced, the need for practical guidelines on switching these medications becomes increasingly important. In this article we provide a short summary of the second-generation antipsychotics, focusing on efficacy, adverse effect profile and safety. Indications for switching antipsychotic medication are outlined, as well as recommendations when switching is disadvantageous. Three basic switching strategies (abrupt, gradual and overlapping switching) and their potential risks and benefits are described. We review the available evidence concerning techniques, problems and consequences when switching from one second-generation antipsychotic agent to another and discuss potential difficulties.

Osteoporosis in patients with schizophrenia.

OBJECTIVE: Osteoporosis is regularly mentioned as a possible consequence of treatment with prolactin-increasing antipsychotic medications, but little is known about the prevalence and the degree of loss of bone mineral density in patients suffering from schizophrenia. The authors' goals were to investigate the association between schizophrenia and a decrease in bone mineral density and to get more insight into potential underlying pathophysiological mechanisms. METHOD: In a cross-sectional study, the authors used dual x-ray absorptiometry to determine bone mineral density of 75 inpatients and outpatients suffering from schizophrenia. All patients had been treated with antipsychotics for at least 1 year, and only patients between the ages of 19 and 50 were studied to exclude patients with age-related idiopathic osteoporosis. RESULTS: In men but not women with schizophrenia, bone mineral density was significantly lower than normal in the lumbar region. A comparison of loss of bone mineral density in male and female patients showed significant differences between the sexes. Bone mineral density showed a negative correlation with negative symptoms and Positive and Negative Syndrome Scale total score and a positive correlation with 25-hydroxy-vitamin D3 levels and body mass index in male patients. In female patients, a positive correlation between body mass index and bone mineral density was found. Exposure to prolactin-increasing antipsychotics was not related to bone mineral density. CONCLUSIONS: The male patients with schizophrenia in this study suffered from low bone density. This finding as well as other reports lend support to directing more attention to bone metabolism in patients with schizophrenia, although there is no universally accepted screening policy to identify individuals at high risk for osteoporosis.

The generic alternative in schizophrenia: opportunity or threat?

Pharmacological treatment of schizophrenia often requires careful dosage titration to achieve satisfactory symptom control whilst minimising the risk of adverse effects. Relapses requiring hospitalisation are an important potential source of additional cost for the health service and any inadequate symptom control increases the indirect costs of schizophrenia relating to, for example, the need for sheltered accommodation or intensive social services support. The availability of generic drugs is widely regarded as an opportunity to reduce expenditure on drug costs and deploy limited resources more widely and effectively. However, generic drugs may differ from branded drugs in their formulation and may not show precise bioequivalence with the branded product. This may have consequences for the pharmacokinetic profile of the generic drug. A higher maximum plasma concentration (C(max)) could lead to increased or emergent adverse effects, whereas a decreased absorption or minimum plasma concentration (C(min)) may result in a reduced therapeutic effect. For example, plasma levels of clozapine are critical to therapeutic response. Symptom aggravation occurred in approximately 10% of patients switched from branded to generic clozapine in a small, randomised, crossover study. Patients with schizophrenia may also show suspicion and hostility regarding their treatment. This may result in unwillingness to take an unfamiliar medication and decreased compliance, thus increasing the risk of a relapse. Thus, great care should be taken by psychiatrists when switching patients with schizophrenia from branded to generic antipsychotic drugs; this entails monitoring clinical outcome closely and adjusting the treatment in case of symptom aggravation or emergence of adverse effects.

Compliance in schizophrenia: psychopathology, side effects, and patients' attitudes toward the illness and medication.

OBJECTIVE: In a cross-sectional study, we investigated the influence of several factors on compliance in schizophrenia outpatients, including patients' attitudes toward the illness and medication, specifically antipsychotic medication; adverse effects; and attitudes of caregivers and relatives toward the illness and medication. METHOD: Patients suffering from schizophrenia (ICD-10 diagnosis) of at least 1-year's duration whose discharge from an inpatient ward was at least 6 weeks prior to inclusion in the study were investigated. Study instruments included a semi-structured compliance interview, the Positive and Negative Syndrome Scale, the Udvalg for Klinske Undersogelser Side Effect Rating Scale, the St. Hans Rating Scale, and the Hillside Akathisia Scale. Data were collected from May 1998 to December 2001. RESULTS: 52.5% (N = 32) of the 61 investigated patients were fully compliant, 39.3% (N = 24) were partially compliant, and only 8.2% (N = 5) were noncompliant. We found positive correlations between compliance and the patients' feelings of a positive effect of the drug on the illness, between compliance and negative symptoms, and between compliance and antipsychotic-induced psychological side effects. CONCLUSION: Our findings reemphasize the importance of taking subjective attitudes and concerns of patients with respect to their illness and medication seriously. Therefore, it is indispensable to include patients and, if possible, their relatives in the treatment decision process to enhance medication compliance in schizophrenia patients.