Efficacy and safety of the sigma receptor ligand EMD 57445 (panamesine) in patients with schizophrenia: an open clinical trial.

EMD 57455 (panamesine) is a new sigma receptor ligand alleged to have antipsychotic effects. Animal studies have demonstrated that EMD 57445 has a functional antidopaminergic activity without extrapyramidal side effects and a c-fos expression pattern similar to that obtained with atypical neuroleptics. Therefore, the substance might be of interest for the treatment of schizophrenia. The present article describes the results of an exploratory open clinical trial that was aimed at determining the appropriate dose range for clinical efficacy and safety of EMD 57455 in patients with an acute episode of schizophrenia. In a treatment period of 4 weeks, 12 patients received EMD 57445 up to 60 mg/day for 4 weeks. Seven patients completed the study: four were classified as responders (as defined by at least a 50% decrease in the BPRS total score), two improved slightly and one patient remained unimproved. The intent-to-treat analysis showed significant improvement in the psychometric variables assessed by the Brief Psychiatric Rating Scale, Clinical Global Impression and Positive and Negative Symptoms Scale. Major side effects were extrapyramidal symptoms in two patients and restlessness in one patient. With respect to efficacy and safety, our data agree with a previous study, except that in our study EMD 57455 was not totally free of extrapyramidal side effects.     

Cholecystokinin-octapeptide in chronic schizophrenia: A double-blind placebo-controlled study

1. Antipsychotic properties of cholecystokinin have been suggested both in laboratory studies and in some open clinical trials, mainly in patients suffering from chronic schizophrenia.

2. Eighteen patients (14 males, 4 females) meeting Research Diagnostic Criteria for schizophrenia had been receiving neuroleptics at a dosage that had not changed for 3 months, and to which the patients were at best only partially responsive.

3. The patients were randomized into groups that received weekly intravenous injections of 10 μg of CCK-8 or normal saline over 8 weeks. Neuroleptic medication was unchanged for the study. Baseline and weekly assessments were carried out using the Brief Psychiatric Rating Scale (BPRS) and the Schizophrenia Subscale of the Present State Examination (SS-PSE).

4. Analysis of covariance revealed significant differences between CCK-8 and placebo over the study period on the Thought Disturbance Factor and Total Score of the BPRS, and on the Nuclear Syndrome, Total Delusion Factor, and Total Score of the SS-PSE.

5. No important side effects were noted.

6. It is concluded that CCK-8 has definite antipsychotic properties in patients with chronic schizophrenia. Clinical trials in neurolept ic-free patients are warranted.     

阿立哌唑与氟哌啶醇治疗精神分裂症对照研究

目的:评价阿立哌唑与氟哌啶醇治疗精神分裂症的疗效及安全性。方法:阿立哌唑组50例,氟哌啶醇组48例,以阳性与阴性症状量表(PANSS)、临床疗效总评量表疾病严重程度(CGI-SI)、治疗中出现的症状量表(TESS)、锥体外系反应量表(RSESE)评定疗效及不良反应。疗程6周。结果:两组疗效相仿。阿立哌唑组PANSS阴性症状因子减分在治疗后4及6周显著优于氟哌啶醇组。阿立哌唑组不良反应显著较少。结论:阿立哌唑是一有效安全的抗精神病药。     

Relationship between class I and II HLA antigens in schizophrenia and eye movement disturbances: a preliminary study

The region coding human leukocyte antigen (HLA) on chromosome 6q21 was shown to be associated with both the vulnerability to schizophrenia and presence of eye movement disturbances (EMD). The aim of this preliminary study was to investigate how individual class I and II HLA antigens in schizophrenic patients may be related to schizophrenia and to the intensity of two kinds of EMD: fixation and smooth pursuit. The incidence of HLA antigens was compared between 40 schizophrenic patients (17 male, 23 female) and 198 healthy control subjects (112 male, 86 female). In schizophrenic patients, the intensity of EMD assessed by infrared reflectometry and quantified on a scale from 0 to 3 was correlated with the incidence of HLA antigens. A number of differences regarding HLA antigens were found between schizophrenic patients and healthy subjects. Significant correlation was also obtained between some EMD and a number of HLA antigens. Antigens A24 and A28 were found to occur in different frequencies in schizophrenic patients and healthy control subjects. They also correlated with EMD on the fixation and smooth pursuit tests. The results obtained show an association between HLA antigens and EMD as an endophenotypic marker of schizophrenia, and may add to other findings on susceptibility loci for schizophrenia on chromosome 6p21. A limitation of this study is a small number of investigated patients with schizophrenia.     

Psychoeducation as an indispensable complement to pharmacotherapy in schizophrenia

Antipsychotic drugs are the most effective medication for the treatment of schizophrenia. Their side effects, however, affect most patients; some of them suffer from them for the rest of their lives, with little chance of improvement. In general, the side effects are perceived differently by patients, their relatives, psychiatrists, and the public. Being informed about the side effects of antipsychotics does not negatively affect compliance and is essential for establishing patients' confidence in doctors and in the medication.     

Is Rational Antipsychotic Polytherapy Feasible? A Selective Review

Antipsychotic polytherapy (APT) has evolved as a common treatment strategy at odds with recommendations from schizophrenia treatment guidelines. The literature on combinations with clozapine as a means to enhance efficacy and with aripiprazole to reduce side effects was reviewed. No solid evidence supporting antipsychotic combinations with clozapine for treatment-resistant patients with schizophrenia was identified. The reason for this may be that most combinations with clozapine increase the D₂-receptor blockade, and this strategy is probably not efficient for patients with treatment-resistant schizophrenia. Some basic and clinical evidence for the addition of aripiprazole to lower prolactin levels was identified. In conclusion, there is very limited support in the evidence for the feasibility of rational APT.     

Iatrogenic Disorders Associated with Conventional vs. Atypical Antipsychotics

Pharmacotherapy is an indispensable component of the management of schizophrenia and related psychotic disorders. Antipsychotic drugs are used for their efficacy in controlling the symptoms of psychosis. However, the side effects of antipsychotic drugs can have a deleterious impact on the course of the illness by inducing iatrogenic symptoms of various severity. The side effects of first-generation or conventional antipsychotic drug were often so intolerable to patients with schizophrenia that their compliance was consistently poor, leading to frequent relapse, chronicity, and impaired functioning. The second-generation (atypical) antipsychotics, introduced 40 years after the advent of the older-generation, are proving to have better outcomes in psychosis not only because of broader symptom efficacy but also because their side-effect profile is more tolerable, leading to higher compliance and fewer relapses. The authors review the side effects of the old and the new antipsychotics and conclude that the improved tolerability of the new antipsychotics is associated with greater effectiveness, not just efficacy. Differences in tolerability among the new antipsychotics are described.     

Antipsychotic efficacy of the dopaminergic autoreceptor agonist EMD 49980 (Roxindol). Results of an open clinical study.

EMD 49980 is a dopamine agonist with selective affinity to dopamine autoreceptors. Following pharmacological findings in animal studies, it was postulated that a hyperactivity of dopaminergic neurons, which is possibly present in acute schizophrenia, may be reduced by autoreceptor stimulation. To investigate the antipsychotic efficacy of EMD 49980, 20 acutely ill schizophrenics (ICD No. 295.3) were treated over four weeks with dosage increasing up to 3 mg or 9 mg. According to previously defined criteria four patients were clear responders, but clinically none of them revealed a full remission. Ten patients were nonresponders, and three of these patients were drop-outs because of marked deterioration of schizophrenic symptoms. The explorative analysis of BPRS subscales shows a statistically significant reduction of anxiety/depression and anergia, but no clear influence on the subscales THOT, HOST, and ACTV, which are the more specific scales for acute schizophrenia. EMD 49980 was subjectively well tolerated and there was no case of drug-induced extrapyramidal side-effects. In view of the only moderate antipsychotic efficacy in acute schizophrenia and the fact that antidepressant and anxiolytic effects were also observed, a clinical investigation of EMD 49980 in affective disorders and in schizophrenia with depression or anergia should be performed.     

Components and correlates of family burden in schizophrenia

OBJECTIVE: Components and correlates of caregiver burden in schizophrenia were studied. METHODS: The family caregivers of 623 (43 percent) of 1,460 patients with schizophrenia enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) were interviewed about resources they provided and experiences with patient behavior over the previous month. Patients were independently evaluated on symptoms, quality of life, neurocognition, medication side effects, and service use. Factor analysis reduced the caregiver data into four orthogonal factors assessing perceptions of patient problem behavior, patient impairment in activities of daily living, patient helpfulness, and resource demands and disruptions in the caregiver's personal routine. RESULTS: Hierarchical regression analyses demonstrated differential correlates of burden for each factor, explaining 34 percent of variance each for problem behavior and resource demands and disruption, 21 percent for impairment in activities of daily living, and 38 percent for patient helpfulness. Demographic characteristics and patient symptoms explained the greatest proportion of variance, whereas quality of life and service use explained modest variance and patient neurocognition and medication side effects were not significantly associated with burden. CONCLUSIONS: Results underscore the need for continued intervention with family members after the acute inpatient phase of treatment to address the impacts of symptoms as well as incorporation of skills training into consumer treatment programs to improve consumer contributions to household maintenance.     

Adherence assessments and the use of depot antipsychotics in patients with schizophrenia

BACKGROUND: Antipsychotic medications significantly ameliorate the symptoms of schizophrenia, but patients are often noncompliant with these medications. Research evidence supports the use of depot antipsychotics in noncompliant patients. METHOD: Between January 9, 1991, and December 19, 1995, 1307 veterans with schizophrenia or schizoaffective disorder (ICD-9) were enrolled in a study of enhanced psychosocial programming at 14 Veterans Administration Medical Centers. All had a history of high inpatient use. At enrollment, clinicians listed patient medications, rated patient compliance, and completed a Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Functioning (GAF). Patients reported medication side effects. We describe depot antipsychotic use among these patients and examine the relationship between depot use, assessed compliance, and patient characteristics. RESULTS: At enrollment, 18% of patients in this cohort were receiving depot antipsychotics; however, clinicians reported that 49% had been noncompliant with medication in the past year. Depot use varied significantly with treatment site; African Americans were more likely to receive depot antipsychotics and less likely to receive atypical antipsychotics than white patients. Patients on depot and oral agents had similar levels of psychiatric symptoms, but patients on depot antipsychotics were more likely to receive high doses and complain of side effects. CONCLUSION: Clinicians prescribed depot antipsychotics relatively infrequently, despite high rates of noncompliance and high levels of inpatient use. Variation in use with treatment site and ethnic group suggests barriers to implementing research-based recommendations for depot use in noncompliant patients. Quality improvement programs should consider facilitating the appropriate use of depots.     

Subchronic effects of olanzapine on sleep EEG in schizophrenic patients with predominantly negative symptoms

BACKGROUND: It is well known that sleep disturbance is an integral symptom of schizophrenia. In recent studies, a deficit of delta sleep has been observed in schizophrenic patients. Antipsychotic drugs with serotonin (5-HT2) receptor-antagonistic properties are considered to have delta sleep promoting effects. We have investigated the effects of subchronic olanzapine treatment on sleep EEG in schizophrenic patients. METHODS: The effects of administration of olanzapine (15 to 20 mg) on sleep were studied for four weeks in 10 male, drug-free patients suffering from schizophrenia with predominantly negative symptoms. Conventional sleep EEG parameters were investigated at baseline and after treatment with olanzapine for four weeks. Additionally, spectral power analysis of the EEG signal in distinct frequency bands was computed for different sleep stages. Psychopathology (PANSS, HAMD-17, HAMA) and side effects were assessed weekly. RESULTS: All patients improved, as measured by PANSS global scores. Compared to baseline, there was a significant improvement of parameters of sleep efficiency and an increase of delta sleep as well as REM sleep. Regarding spectral power values, no significant differences between baseline and treatment conditions were found. CONCLUSIONS: Sleep improvement was due to parameters of sleep efficiency and delta sleep, which may be related to serotonin antagonistic properties of olanzapine.     

Treatment of schizophrenia patients: comparing new-generation antipsychotics to each other

PURPOSE OF REVIEW: Although the debate on whether new antipsychotics have advantages over the old neuroleptics has recently been refueled by the first publication of the Clinical Antipsychotic Trials of Intervention Effectiveness results, one of the new challenges in the pharmacological management of schizophrenia patients is to choose among the new-generation drugs. RECENT FINDINGS: Earlier work has compared these medications primarily to traditional antipsychotics and until very recently there was little published information on the relative efficacy/safety of new-generation antipsychotics. SUMMARY: This review covers studies wherein therapeutic effects and adverse events of these drugs in schizophrenia patients were compared in head-to-head studies and that were published in 2005. Information is clearly more homogenous on the safety profile side, while the available evidence still offers little help for the clinicians' daily struggles to find the optimally effective antipsychotic for an individual schizophrenia patient.     

Is antipsychotic medication stigmatizing for people with mental illness?

Antipsychotic medications are clearly identified as important in the treatment of individuals with schizophrenia and with bipolar disorder. However, negative societal reaction related to having a serious mental illness and the socially undesirable side effects associated with antipsychotic medication treatment may combine to worsen stigma associated with treatment for mental illness. Specific stigmatizing effects of antipsychotic therapy may be difficult to evaluate independently from factors such as symptoms, insight into illness and side effects. Attitudes towards antipsychotic medication may be positive in individuals who recognize therapeutic drug effects, however other individuals may view medications negatively due to a sense of stigma. Stigma among individuals with bipolar disorder in relation to treatment with antipsychotic medication has not been well addressed in the literature. An additional concern among individuals with bipolar disorder who receive antipsychotic medications may be the notion that antipsychotics are 'schizophrenia drugs', and thus an inappropriate treatment for their condition. Antipsychotic medications can be stigmatizing for patients with serious mental illness, however the roots of stigma are extensive, and efforts to minimize stigma can only be successful when addressed by the individual with illness, their families and loved ones, treatment providers and society at large.     

Risperidone treatment of outpatients with schizophrenia: no evidence of sex differences in treatment response.

OBJECTIVE: Given the renewed interest in the role of sex differences in schizophrenia, we undertook a post hoc analysis to determine whether sex differences in treatment response were present among outpatients with schizophrenia who received risperidone in an 8-week, open-label, Phase IV clinical study. METHOD: We evaluated 330 adult patients (232 men, 98 women) with a DSM-III-R diagnosis of schizophrenia for safety and 292 (206 men, 86 women) for efficacy. Antipsychotic and antiparkinsonian medications were discontinued at study entry. Treatment with risperidone was initiated at a dosage of 2 mg daily, increased to the target dosage of 6 mg daily by day 3, and maintained at 6 mg daily until day 14. The dosage was then maintained at 6 mg daily, increased or decreased by 2 mg daily each week, based on the patient's response. Risperidone treatment was given for 8 weeks; the permitted dosage range was 4 mg to 10 mg daily. RESULTS: Both male and female participants responded well to risperidone treatment; by the final assessment day, they had experienced decreases from baseline in their total Positive and Negative Syndrome Scale (PANSS) scores of 41.0% and 36.5%, respectively. Most male (77%) and female (78%) participants were considered to be PANSS responders: risperidone was effective against both the positive and negative symptoms of schizophrenia. Both sexes showed improvements over baseline in the incidence and severity of parkinsonism, dystonia, and dyskinesia. No significant (P > 0.05) sex differences in treatment response were observed for any of the efficacy outcomes or in the incidence and severity of extrapyramidal symptoms (EPS). CONCLUSIONS: In this population of outpatients with chronic schizophrenia, both men and women responded well to flexible doses of risperidone. No significant sex differences were evident either in treatment response or in neurological side effects. The absence of sex differences in response to risperidone treatment may obviate the need for a sex-based differential dosing in schizophrenia management.     

Sensorimotor dysfunction of grasping in schizophrenia: a side effect of antipsychotic treatment?

BACKGROUND: Antipsychotic treatment in schizophrenia is frequently associated with extrapyramidal side effects. Objective behavioural measures to evaluate the severity of extrapyramidal side effects in the clinical setting do not exist. OBJECTIVES: This study was designed to investigate grasping movements in five drug naive and 13 medicated subjects with schizophrenia and to compare their performance with that of 18 healthy control subjects. Deficits of grip force performance were correlated with clinical scores of both parkinson-like motor disability and psychiatric symptom severity METHODS: Participants performed vertical arm movements with a handheld instrumented object and caught a weight that was dropped into a handheld cup either expectedly from the opposite hand or unexpectedly from the experimenter's hand. The scaling of grip force and the temporospatial coupling between grip and load force profiles was analysed. The psychiatric symptom severity was assessed by the positive and negative symptom score of schizophrenia and the brief psychiatric rating scale. Extrapyramidal symptoms were assessed by the unified Parkinson's disease rating scale. RESULTS: Drug naive subjects with schizophrenia performed similar to healthy controls. In contrast, medicated subjects with schizophrenia exhibited excessive grip force scaling and impaired coupling between grip and load force profiles. These performance deficits were strongly correlated with the severity of both extrapyramidal side effects related to antipsychotic therapy and negative symptoms related to the underlying pathology. CONCLUSIONS: These data provide preliminary evidence that deficits of sensorimotor performance in schizophrenia are, at least in part, related to the side effects of antipsychotic treatment. The investigation of grasping movements may provide a sensitive measure to objectively evaluate extrapyramidal side effects related to antipsychotic therapy.     

Does Long-Term Treatment of Schizophrenia With Antipsychotic Medications Facilitate Recovery?

Antipsychotic medications are viewed as cornerstones for both the short-term and long-term treatment of schizophrenia. However, evidence on long-term (10 or more years) efficacy of antipsychotics is mixed. Double-blind discontinuation studies indicate significantly more relapses in unmedicated schizophrenia patients in the first 6-10 months, but also present some potentially paradoxical features. These issues are discussed.Key words: psychosis, longitudinal studies, unmedicated patients, outcome     

Sensitivity to Antipsychotic Drugs in Older Adults

Antipsychotic medications are widely used to manage psychotic and behavioral disorders in older adults, including primary psychotic disorders such as schizophrenia, and psychosis and behavioral disturbances associated with dementia. These two broad diagnostic indications are associated with contrasting recommended treatment durations, with the former requiring indefinite treatment across the life span. Antipsychotic drug dosing for schizophrenia is based primarily on studies of younger patients and thus may not apply to older adults. It is critically important to address the effects of aging on antipsychotic dosing given the recent emergence of data that suggest a critical role for age-related sensitivity to these drugs. Antipsychotic drugs are not only associated with somatic and neurological adverse effects but also increased all-cause mortality and sudden cardiac death in this vulnerable population. This review focuses on the sensitivity of older adults to adverse effects from antipsychotic medications and the current pharmacokinetic and pharmacodynamic explanatory models of susceptibility. Implications of recent research findings for individualized pharmacotherapy are discussed.     

阿立哌唑治疗精神分裂症病人的疗效观察

目的观察阿立哌唑治疗精神分裂症病人的疗效和不良反应。方法46例精神分裂症病人用阿立哌唑治疗6周，用BPRS评定疗效、TESS评定不良反应。结果阿立哌唑对精神分裂症病人有较好的疗效，主要不良反应为轻度的锥体外系反应、头痛、焦虑和失眠。结论阿立哌唑治疗精神分裂症病人疗效肯定，安全性高，值得临床试用。     

Weight gain from novel antipsychotic drugs: need for action

Obesity is common in schizophrenia, and people with schizophrenia appear to be at increased risk for certain obesity-related conditions, such as type 2 diabetes and cardiovascular disease. Antipsychotic drugs, used chronically to control symptoms of schizophrenia, are associated with often-substantial weight gain, a side effect that is a special concern with the latest generation of highly effective "novel" agents. That the most effective (e.g., novel) antipsychotic medications lead to substantial weight gain presents the field with a critical public health problem. Although preliminary data have been reported regarding the beneficial use of behavior therapy programs for short-term weight control in patients with schizophrenia, the available data are quite limited, and there are no data regarding the long-term beneficial effects of these programs in this population. The obesity field recently has developed programs emphasizing "lifestyle changes" (e.g., diet, exercise, and problem-solving skills) to successfully manage weight in patients without schizophrenia. Such programs can be adapted for patients with schizophrenia through the use of highly structured and operationalized modules emphasizing medication compliance, social skills development, and participation in outpatient programs. Moreover, these programs can potentially be combined with the use of adjunctive pharmacotherapy to maximize and maintain weight loss. The field must solve the paradox that some of our most effective medications for schizophrenia produce substantial weight gain and its associated troubling health risks.