Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis

Department of Psychiatry University of Oxford, Warneford Hospital, Oxford OX3 7JX.
BMJ Clinical Research (Impact Factor: 14.09). 01/2001; 321(7273):1371-6. DOI: 10.1136/bmj.321.7273.1371
Source: PubMed

ABSTRACT To develop an evidence base for recommendations on the use of atypical antipsychotics for patients with schizophrenia.
Systematic overview and meta-regression analyses of randomised controlled trials, as a basis for formal development of guidelines.
12 649 patients in 52 randomised trials comparing atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with conventional antipsychotics (usually haloperidol or chlorpromazine) or alternative atypical antipsychotics.
Overall symptom scores. Rate of drop out (as a proxy for tolerability) and of side effects, notably extrapyramidal side effects.
For both symptom reduction and drop out, there was substantial heterogeneity between the results of trials, including those evaluating the same atypical antipsychotic and comparator drugs. Meta-regression suggested that dose of conventional antipsychotic explained the heterogeneity. When the dose was </=12 mg/day of haloperidol (or equivalent), atypical antipsychotics had no benefits in terms of efficacy or overall tolerability, but they still caused fewer extrapyramidal side effects.
There is no clear evidence that atypical antipsychotics are more effective or are better tolerated than conventional antipsychotics. Conventional antipsychotics should usually be used in the initial treatment of an episode of schizophrenia unless the patient has previously not responded to these drugs or has unacceptable extrapyramidal side effects.

Download full-text


Available from: Paul E Bebbington, Jul 01, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Typical antipsychotics are characterized by extrapyramidal syndrome (EPS). Previous studies demonstrated that typical antipsychotics could inhibit neuronal voltage-gated sodium channel (VGSC). However, EPS typically emerge only upon prolonged exposure. As a result, we examined effects of haloperidol, a prototype typical antipsychotic, on neuronal VGSC upon incubation for varying duration. Briefly, VGSC currents were activated and recorded using a whole-cell patch-clamp technique in primary culture of mouse cortical neurons. VGSC activity was inhibited by acute haloperidol exposure (for minutes), but enhanced in a time- and concentration-dependent manner by chronic haloperidol exposure (for hours). The effects of chronic haloperidol were associated with increased expression of VGSC subunits as well as corresponding electrophysiological channel properties. In summary, we found enhanced VGSC currents upon chronic haloperidol exposure in cortical neurons in contrast to inhibition by acute haloperidol exposure. Such a results may contribute to EPS of typical antipsychotics.
    Biochemical and Biophysical Research Communications 05/2014; 450(1). DOI:10.1016/j.bbrc.2014.05.081 · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Results of meta-analyses are regarded as the highest level of evidence. A statistically non-significant effect size from a meta-analysis is typically considered true negative even in the presence of a statistically significant signal in individual studies, presumed to be false positive. Here we provide examples from neuroimaging, genetics and psychopharmacology of why meta-analyses may frequently yield false negative results from true positive findings. This may happen in situations when individual studies report findings in opposing directions, the sum of which yields a non-significant overall effect size. Such non-significant meta-analyses, which show statistical heterogeneity and include studies with opposing effect sizes do not provide an accurate estimate of the overall effect and may have lower heuristic value than individual studies. Over reliance on such meta-analyses may falsely identify certain potentially fruitful research avenues as blind alleys.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 02/2013; 23(10). DOI:10.1016/j.euroneuro.2013.01.004 · 5.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We hypothesize the interaction between antipsychotic medications and regulation of extracellular glutamate which has gone largely unnoticed in the medical community has significant clinical importance. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate because they exert antagonist effects on dopamine D(2) and serotonin 5HT(1A) receptors. In contrast, serotonin 5HT(2A) receptor antagonists inhibit glutamate release. Glutamate is potentially excitotoxic through effects on ionotropic receptor channels and may exert synergistic effects with other neurotoxic pathways. In contrast to typical antipsychotic drugs, pharmacological properties of atypical antipsychotic medications at dopamine D(2), serotonin 5HT(1A) and 5HT(2A) receptors limit extracellular glutamate and may theoretically be neuroprotective in certain clinical settings. In this review we discuss three common clinical settings in which typical antipsychotic medications may potentiate neurotoxicity by elevating extracellular glutamate. The most common clinical setting, hypoglycemia during combined use of antipsychotic medications and insulin, presents a theoretical risk for 35 million diabetic patients worldwide using antipsychotic medications. Antipsychotic medication treatment during hypoxic episodes in the intensive care unit and following traumatic brain injury are two other common clinical settings in which this interaction poses theoretical risk. Further study is needed to test hypothesized risk mechanisms, and determine clinical and epidemiological consequences of these exposures.
    Medical Hypotheses 12/2012; DOI:10.1016/j.mehy.2012.11.042 · 1.15 Impact Factor