Background: Optimal treatment of primary negative symptoms is important because their presence is associated with poor outcome. Aims: To systematically review all studies dealing with the efficacy of pharmacological agents on primary negative symptoms. Method: A comprehensive search of the relevant literature was undertaken using electronic database, reference lists and personal contact. Results: There is a lack of standardized research designs. Amisulpride is the most extensively studied drug with respect to efficacy against primary negative symptoms. At low doses it demonstrates a consistent, modest effect compared to placebo, though not to conventional antipsychotics and has yet to be tested against other atypicals. Evidence from multiple studies that used simple statistical analyses and inclusion criteria for patients with primary negative symptoms does not support a direct effect for clozapine. Path-analysis studies support the direct effects of risperidone, olanzapine, sertindole and aripiprazole, however, different statistical analyses of the same risperidone study produced conflicting results and the direct effects of olanzapine were not confirmed in selected patients with primary negative symptoms. There are no studies supporting the use of ziprasidone or quetiapine. The effects of typical antipsychotics on primary negative symptoms are inconclusive and likely to depend on drug dosages. Selective serotonin reuptake inhibitors (SSRIs), mirtazepine and NMDA agonists show early promise but require further study. Novel agents such as selegiline, naltrexone, dehydroepiandrosterone, galantamine, Ginkgo, nitric oxide, l-deprenyl and pergolide show positive effects on general negative symptoms but remain untested against primary negative symptoms. Conclusions: Further studies using standardized selective inclusion criteria and controlling for chronicity are needed. Research guidelines are discussed. © 2006 Elsevier B.V. All rights reserved.
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