should be used as the initial treatment unless a patient has not responded to, or tolerated, an FGAM. However, the National Institute for Clinical Excellence Guidelines on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia () - an evidence-based appraisal - included the following in its guidance recommendations: “It is recommended that the oral atypical antipsychotic drugs amisulpiride, olanzapine, quetiapine, risperidone and zotepine are considered in the choice of first-line treatments for individuals with newly diagnosed schizophrenia” (see Appendix 6).
Chakos et al.  reviewed studies that compared the efficacy and tolerability of FGAMs and SGAMs in treatment-resistant schizophrenia. The results of this meta-analysis indicated that clozapine was superior to FGAMs in efficacy on measures of psychopathology and compliance and in terms of EPSs. However, the magnitude of this effect was not consistently robust. The data on efficacy of other SGAMs in the treatment of patients with refractory schizophrenia was inconclusive.
Leucht et al.  reviewed 18 studies that compared the efficacy and tolerability of amisulpride with placebos and FGAMs. The results indicated that amisulpride was consistently more effective than placebos and FGAMs on global schizophrenic symptoms and negative symptoms. Amisulpride also had lower rates of antiparkinsonian medication usage and fewer drop-outs due to adverse events.
Recent large-scale investigations
The need to obtain relevant data on treatments for mental illness is so great that large-scale investigations of treatment effectiveness have been undertaken by governments and industry. The Clinical Antipsychotic Trials of Intervention Effectiveness, a major research initiative in the US by the National Institute of Mental Health, are assessing the effectiveness of the SGAMs in a broad range of patients with schizophrenia and in patients with Alzheimer’s disease. In Germany, Medical Networks in Medicine has undertaken significant research. A consortium of pharmaceutical companies supports the European First Episode Treatment Study in Schizophrenia. Novartis has recently completed a large international study of suicidal behavior in schizophrenia (InterSePT) . In the US, Pfizer is conducting a large post-marketing cardiac surveillance study (Zodiac).
Despite the relative lack of study of the use of adjunctive medications to augment the effects of antipsychotic drugs, the practice of combining medications is very common. This includes the use of mood-stabilizers, antidepressants, anxiolytics, cholinomimetics or marketed experimental agents (e.g. guanfacine, glycine) with FGAMs and SGAMs and the combination of multiple antipsychotic drugs [212,235].
One of the few controlled studies of combined treatments with SGAMs was recently reported by Casey et al.. This was a 4-week RCT under double blind conditions in which valproate or a placebo was combined with either risperidone or olanzapine in patients with acutely exacerbated schizophrenia