非典型抗精神病药物用于精神分裂症康复期治疗

精神分裂症是一组病因尚未明确的精神疾病,患者具有思维、情感和行为等多方面障碍及精神活动不协调。精神分裂症康复期治疗以药物治疗为基础,旨在减少病情的反复。目前,非典型抗精神病药物(SGA)为精神分裂症一线治疗药物。本文就近年SGA在精神分裂症康复期治疗中的研究进展作一综述。     

Antipsychotic drugs in schizophrenia: current issues

In the 1950s antipsychotic antidopaminergic drugs were introduced as the pharmacological treatment of schizophrenia. In the last 35 years a large fund of knowledge has been acquired about these drugs. Still, a number of issues regarding them require further addressing. We have reviewed the literature on some of these issues, focusing on those factors that the previous studies have resolved inadequately. The issue of optimal dosages of antipsychotics in schizophrenia has been analyzed from the perspective of the dose requirements during "rapid tranquilization", "in acute psychotic phases of schizophrenia", "in chronically hospitalized psychotic schizophrenic patients" and during "maintenance phases of schizophrenia". We have briefly discussed the different methodologies available for measuring neuroleptic levels in plasma, their methodological weaknesses and strengths and some of the larger studies done with chlorpromazine, haloperidol and fluphenazine to establish correlations between levels, treatment response, oral dosages and side-effects. The theoretically fascinating concept of supersensitivity psychosis has been reviewed and the theoretical and practical weaknesses that exist in most of the papers that have claimed validity for this concept are presented. The article also reviews the preclinical, postmortem and clinical research that demonstrates the presence of site selectivity for dopamine receptors in the newer atypical neuroleptics. Finally, the article briefly reviews the current status of some unorthodox clinical strategies, that may be potentially applicable in managing schizophrenic disorders.     

Anti-epileptic drugs in pregnancy: current safety and other issues

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.     

Anti-epileptic drugs in pregnancy: current safety and other issues

Women with epilepsy of child-bearing years have their own considerations, which must be taken into account if management of their epilepsy is to be optimised. The main issues to consider include the effects of: female hormones on seizure control, anti-epileptic drugs (AEDs) on hormonal methods of contraception, epilepsy and AEDs on fertility, epilepsy and AEDs on pregnancy itself, pregnancy on AEDs and seizure control and epilepsy, seizures and AEDs on the developing embryo/fetus. Whereas previous studies have concentrated on the increased risk of major congenital malformations from prenatal AED exposure, the effects on cognitive and behavioural development are increasingly being explored. This article looks at the evidence currently available for all of the above issues, taking into account the increased number of AEDs which are now available.     

Atypical antipsychotic drugs, diabetes and ethnicity

There are 17 million people affected by diabetes in the US. It is a syndrome consisting of metabolic abnormalities, microvascular and macrovascular disease leading to cardiac, renal and neurological abnormalities. Obesity is the most common public health problem in developed nations. Diabetes and obesity-related illnesses are common in ethnic minorities such as African-Americans, Hispanics and Asians related to both genetics and lifestyle patterns. In all ethnic minorities in the US, an increase in Type 2 diabetes has been observed. However, the Asian group experienced the highest rate of increase in prevalence between the years 1990 and 1998. The changing ethnic composition of the US population may contribute significantly to the worsening of the diabetes epidemic in this country. Atypical antipsychotic drugs can induce diabetes, as well as obesity. All atypical antipsychotic drugs can produce diabetes, but drugs such as olanzapine and clozapine have been known to produce diabetes more often than other drugs. As ethnic minority patients including Asians, Hispanics and African-Americans are predisposed to develop diabetes, antipsychotics become a burden by precipitating diabetes. Such a situation poses a problem in treating ethnic minority psychiatric patients. In clinical situations, close monitoring is necessary to prevent metabolic side effects of these drugs.     

Atypical antipsychotic drugs,diabetes and ethnicity

There are 17 million people affected by diabetes in the US. It is a syndrome consisting of metabolic abnormalities, microvascular and macrovascular disease leading to cardiac, renal and neurological abnormalities. Obesity is the most common public health problem in developed nations. Diabetes and obesity-related illnesses are common in ethnic minorities such as African–Americans, Hispanics and Asians related to both genetics and lifestyle patterns. In all ethnic minorities in the US, an increase in Type 2 diabetes has been observed. However, the Asian group experienced the highest rate of increase in prevalence between the years 1990 and 1998. The changing ethnic composition of the US population may contribute significantly to the worsening of the diabetes epidemic in this country. Atypical antipsychotic drugs can induce diabetes, as well as obesity. All atypical antipsychotic drugs can produce diabetes, but drugs such as olanzapine and clozapine have been known to produce diabetes more often than other drugs. As ethnic minority patients including Asians, Hispanics and African–Americans are predisposed to develop diabetes, antipsychotics become a burden by precipitating diabetes. Such a situation poses a problem in treating ethnic minority psychiatric patients. In clinical situations, close monitoring is necessary to prevent metabolic side effects of these drugs.     

Atypical antipsychotic drugs in the treatment of Parkinson's disease

Parkinson's disease (PD) patients often develop psychotic symptoms that severely affect quality of life and limit the use of medications to ameliorate motor symptoms. Psychotic symptoms are a major cause for nursing home placement. While these symptoms do not always require treatment, they often do but antipsychotic drugs all share the common pharmacological mechanism of blocking dopamine D2 receptors which may worsen motor problems in this very vulnerable population. Double blind, placebo controlled trials (DBPCT) have shown that clozapine is effective at controlling the psychotic symptoms at doses far below those used in schizophrenia, without worsening motor function, even improving tremor. DBPCT have demonstrated that olanzapine worsens motor function without improving psychosis. Quetiapine has been shown in DBPCT to be free of motor side effects in PD patients but not effective, whereas many open label studies have indicated that quetiapine is effective. The other atypical have been the subjects of conflicting open label reports. The effects of the atypicals in PD psychosis is reviewed.     

Haematological safety of antipsychotic drugs

Haematological abnormalities are frequently encountered during treatment with antipsychotic drugs. Most of these are mild and of no clinical significance. In the case of many, there is often difficulty in establishing a cause-and-effect relationship between the drug and the abnormality. However, in a small minority of patients, hazardous, potentially life-threatening haematological effects can occur due to a combination of pharmacological and host factors. These include leucopenia and agranulocytosis. Although such effects are rare, it is essential that they are diagnosed and managed promptly. In this paper, the authors review the haematological adverse effects and safety of antipsychotic drugs and present a strategy for prevention.     

Haematological safety of antipsychotic drugs

Haematological abnormalities are frequently encountered during treatment with antipsychotic drugs. Most of these are mild and of no clinical significance. In the case of many, there is often difficulty in establishing a cause-and-effect relationship between the drug and the abnormality. However, in a small minority of patients, hazardous, potentially life-threatening haematological effects can occur due to a combination of pharmacological and host factors. These include leucopenia and agranulocytosis. Although such effects are rare, it is essential that they are diagnosed and managed promptly. In this paper, the authors review the haematological adverse effects and safety of antipsychotic drugs and present a strategy for prevention.     

Haematological safety of antipsychotic drugs

Many clinicians have become concerned about the safety of new antipsychotics particularly in view of the association of agranulocytosis with clozapine and of aplastic anaemia with remoxipride. The Committee on Safety of Medicines and Medicines Control Agency 'yellow card' post-marketing surveillance data were analysed for reports of haemopoietic disorders with the 16 antipsychotics in common use. Corrections for relative risk were made in three separate ways: (i) control for degree of use, using Northern Ireland prescribing data for 1995; (ii) percentage of total reports from 1963 to 1996; and (iii) examination of the first 5 years' post-marketing data only. After clozapine and remoxipride the highest risks of haemopoietic reactions appeared to be associated with the aliphatic phenothiazine derivatives thioridazine and chlorpromazine. There is therefore no evidence of any increased risk with high-potency drugs such as haloperidol or pimozide or with the newer drugs such as sulpiride or risperidone. Continued vigilance, however, is necessary as more new atypicals become available and begin to be widely prescribed.     

Chlorpromazine versus every other antipsychotic for schizophrenia: A systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs

It is one of the major psychiatric dogmas that the efficacy of all antipsychotic drugs is same. This statement originated from old, narrative reviews on first-generation antipsychotics, but this old literature has never been meta-analysed. We therefore conducted a meta-analysis of randomised controlled trials on the efficacy of chlorpromazine versus any other antipsychotic in the treatment of schizophrenia. If the benchmark drug chlorpromazine were significantly more or less effective than other antipsychotics, the notion of equal efficacy would have to be rejected. We searched the Cochrane Schizophrenia Group׳s specialized register, MEDLINE, EMBASE, PsychInfo and reference lists of relevant articles. The primary outcome was response to treatment. We also analyzed mean values of schizophrenia rating scales at endpoint and drop-out rates. 128, mostly small, RCTs with 10667 participants were included. Chlorpromazine was compared with 43 other antipsychotics and was more efficacious than four (butaperazine, mepazine, oxypertine and reserpine) and less efficacious than other four antipsychotics (clomacran, clozapine, olanzapine and zotepine) in the primary outcome. There were no statistically significant efficacy differences between chlorpromazine and the remaining 28 antipsychotics. The most important finding was that, due to low numbers of participants (median 50, range 8–692), most comparisons were underpowered. Thus we infer that the old antipsychotic drug literature was inconclusive and the claim for equal efficacy of antipsychotics was never evidence-based. Recent meta-analyses on second-generation antipsychotics were in a better position to address this question and small, but consistent differences between drugs were found.     

Sertindole: efficacy and safety in schizophrenia

Sertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level. The active substance has a long half-life. Oral administration once daily yields highly stable plasma levels. These features may explain the clinically observed low frequency of extrapyramidal side effects, including tardive dyskinesia. In contrast to most antipsychotics, sertindole seems to be void of sedative effects. However, although not strictly proven by objective neuropsychological tests, this asset of sertindole does not add to the cognitive problems inherent in schizophrenia. Administration of sertindole is more often associated with prolongation of QTc compared with most other currently used antipsychotics. However, large cohort analyses do not suggest that all-cause mortality is higher with sertindole than with, for example, risperidone or olanzapine. The effective antipsychotic dose range of sertindole is 12-20 mg/day, with small variations among patients. The frequency of most adverse events, for example extrapyramidal symptoms and somnolence, with such a dose does not differ from placebo. Three side effects have been more common than with placebo/haloperidol in short-term studies: weight gain, rhinitis and a decreased ejaculation volume. Two head-to-head comparisons (one in treatment-resistant patients) of sertindole and risperidone showed equivalent effects on positive symptoms. For negative symptoms, one study obtained equivalent effects and one a superior effect of sertindole. Sertindole should not be used as first-line treatment for first-episode patients with schizophrenia because of the QTc prolongation. It has a side-effect profile that makes it an interesting alternative for many patients who do not respond well to the initial choice of antipsychotic drug.     

Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine.

The purported advantages of second-generation or "atypical" antipsychotics relative to first-generation antipsychotics have not been examined in patients with a first episode of schizophrenia. This flexible-dose study examined efficacy and safety in a randomized, double-blind, 52-week trial, comparing chlorpromazine (CPZ) and clozapine (CLZ) in treatment naive patients experiencing their first episode of schizophrenia. In all, 160 inpatients with first-episode schizophrenia or schizophreniform disorder were randomized to CPZ or CLZ and followed them for 52 weeks or until dropout. The primary efficacy measure was time to first remission and proportion of time remaining in remission. The analysis was supplemented by comparisons on a profile of clinical symptoms and side effects. Of these first-episode patients, 80% achieved remission within 1 year (79% CPZ, 81% CLZ). The Kaplan-Meier estimated median time to first remission was 8 weeks for CLZ vs 12 weeks for CPZ (chi(2)(1)=5.56, p=0.02). Both the rate of first achieving remission and the odds for being in remission during the trial were almost doubled for the CLZ group in comparison with the CPZ group. At 12 weeks, CLZ was superior on many rating scale measures of symptom severity while CPZ was not superior on any. These symptom differences remained significant when controlling for EPS differences. By 52 weeks many of the symptom differences between groups were no longer significantly different. Generally, CLZ produced fewer side effects than CPZ, particularly extrapyramidal side effects. There was no significant difference between treatments in weight change or glucose metabolism. For each prior year of untreated psychosis, there was a 15% decrease in the odds of achieving remission (OR=0.85; CI 0.75-0.95). A high proportion of first-episode patients remitted within 1 year. We detected no difference in the proportion of first-episode patients receiving CLZ or CPZ that achieved remission. However, first-episode patients receiving CLZ remitted significantly faster and remained in remission longer than subjects receiving CPZ. While the CLZ group showed significantly less symptomatology on some measures and fewer side effects at 12 weeks, the two treatment groups seemed to converge by 1 year. Longer duration of untreated psychosis was associated with lower odds of achieving remission.     

Sertindole: efficacy and safety in schizophrenia

The most commonly prescribed class of medications in the United States for chronic severe pain is opioid analgesics. Due to their low cost and widespread availability, the synthetic opioids are popular choices among clinicians and patients. However, there is an increasingly recognized risk of QT prolongation with several drugs in this class, and recently propoxyphene (Darvon) was withdrawn from the market by the Food and Drug Administration (FDA) due to, in part, the risk of QT prolongation and ventricular arrhythmias Updated Epidemiological Review of Propoxyphene Safety. [FDA Alert]. Rockville, MD: U.S. Food and Drug Administration; 2010. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM234383.pdf on 5 May 2012.     

Atypical antipsychotic drugs and organization of long-term semantic memory: multidimensional scaling and cluster analyses of category fluency performance in schizophrenia

Organization of semantic memory, one of the domains of cognitive function, is impaired in patients with schizophrenia, and is predictive of functional outcomes. The Category Fluency Task (CFT) has been used to evaluate organization of long-term semantic memory by means of visualizing semantic associations in the form of 'cognitive map' and cluster structures. While atypical antipsychotic drugs (AAPDs) have been shown to ameliorate overall cognitive deficits, little is known about the efficacy of AAPDs for improving higher cognitive functions, such as semantic memory organization. The purpose of the present study was to determine if treatment with olanzapine or ziprasidone has beneficial influence on organization of semantic memory, as revealed by analysis of data from the CFT, in patients with schizophrenia. A retrospective analysis of an open-label trial was conducted for 33 patients with schizophrenia who were treated with either olanzapine or ziprasidone. Nineteen subjects were unmedicated at baseline. The CFT and Letter Fluency Task, as well as the Brief Psychiatric Rating Scale (BPRS) and Quality of Life Scale (QLS), were administered at baseline and 6 wk of the treatment. Semantic structures were obtained by multidimensional scaling analysis and hierarchical cluster analysis of verbal outputs from the CFT. At baseline, no meaningful dimension or cluster was observed in the semantic structure; however, knowledge-based dimensions (wild vs. domestic) appeared after treatment with olanzapine or ziprasidone. Cluster structures also became organized, especially after treatment with olanzapine. Scores of QLS, but not those of BPRS, improved during treatment with the AAPDs. These results suggest a facilitative influence of AAPDs on higher cognitive functions, such as organization of semantic memory, in patients with schizophrenia.     

Atypical antipsychotic drugs block selective components of amphetamine-induced stereotypy

Individual items of behavior produced by 1.0 or 5.0 mg/kg d-amphetamine were monitored in rats pretreated 15 minutes earlier with vehicle or with behaviorally relevant doses of haloperidol (0.1 or 0.25 mg/kg), clozapine (1.0 or 5.0 mg/kg), or thioridazine (1.0 or 5.0 mg/kg). Unlike haloperidol, the atypical antipsychotics failed to block all components of either the low- or high-dose response to amphetamine. These drugs, however, did block selective items of amphetamine-induced stereotyped behavior. Clozapine significantly attenuated the sniffing produced by 1.0 mg/kg d-amphetamine as well as the oral behavior (licking and/or biting) produced by 5.0 mg/kg d-amphetamine. Thioridazine, at a dose of 5.0 mg/kg, also reduced oral behavior and selectively blocked repetitive head bobbing. Taken together, these results suggest that although atypical antipsychotic drugs exert some common effects on the amphetamine behavioral response, these drugs do not influence all amphetamine-induced behaviors equally.     

Atypical antipsychotic drugs and tardive dyskinesia: relevance of D2 receptor affinity

Evidence suggests atypical antipsychotic treatment is associated with a lower incidence of tardive dyskinesia (TD) than typical antipsychotic drugs, and is a potential antidyskinetic treatment. We present the case of a middle-aged woman never previously exposed to antipsychotic treatment who developed TD after 6 months of olanzapine monotherapy. Substitution of quetiapine for olanzapine alleviated her TD symptoms. The case demonstrates that atypical antipsychotic drugs have different effects in relation to TD. Potential psychopharmacological mechanisms explaining these differences are discussed, highlighting the importance of D2 receptor occupancy by atypical antipsychotic drugs for TD.     

Current schizophrenia drugs: efficacy and side effects

Over the course of the past decade, the acceptance of several second-generation antipsychotics (SGAs) as effective medication for the treatment of schizophrenia has led to some changes. SGAs have a lower risk of inducing extrapyramidal side effects and tardive dyskinesia compared with first-generation antipsychotics, and have been said to be more successful in long-term treatment and tolerability. They also significantly improve the quality of life of schizophrenic patients. However, during treatment with SGAs other adverse effects can occur, such as weight gain, metabolic changes, sexual dysfunction and QTc-prolongation, significantly affecting the patient’s physical health. Consequently, these side effects might be the reason that a high proportion of patients discontinue treatment with SGAs. Thus, from the authors’ view, optimising individualised treatment implies increasing the efficacy of current schizophrenia drugs. This can be achieved by finding clinical or pharmacogenetic predictors for the most appropriate drug or drug combination, and by improving side-effect management in combination with non-pharmacological interventions in order to increase patients’ quality of life and treatment compliance, possibly resulting in a better long-term outcome.