Several literature reviews and meta-analyses have been published in recent years, which have attempted to determine the extent to which various drugs and drug classes differ in their efficacy.9,14,15
It appears that in the treatment of acute psychosis among patients with first-episode or recent-onset illness that there are not significant differences in overall response rates of psychotic signs and symptoms with different antipsychotic drugs or drug classes.16-19
In general, response rates among such patients are quite high.
However, in the maintenance phase of treatment following acute response among first-episode patients, differences do begin to emerge favoring second-generation medications, incuding olanzapine and risperidone,19-22
as well as amisulpride, quetiapine, and ziprasidone.19
In the treatment of multiepisode patients the picture becomes more complicated. The enthusiasm with which the second-generation drugs were received was fueled by unmet need, a long period without any new antipsychotics, vigorous marketing, and to some extent “wishful thinking” as clinicians would also like to believe that they have new and better tools with which to help their patients.
Over time as the cost of medications escalated, intense debate ensued about the relative merits of the different drugs and drug classes. Large “effectiveness” studies such as CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness),17
CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia),3,24
and EUFEST (European First Episode Schizophrenia Trial)19
were intended, to some extent, to clarify this issue.
The data from these trials must be considered along with the data from all other trials which have been the subject of a series of meta-analyses. Single studies, no matter how large, and meta-analyses, no matter how comprehensive, all have their limitations, but it is incumbent upon us to assimilate, objectively integrate and draw relevant conclusions from the evidence, such as it is.
In comparing first and second-generation antipsychotics (FGAs and SGAs),9
Leucht et al found four SGAs (amisulpride, clozapine, olanzapine, and risperidone) to be more efficacious than FGAs with effect sizes ranging from small to medium (0.13 for risperidone and 0.52 for clozapine). Leucht et al emphasized that the SGAs which were more efficacious showed these advantages for both of the specific domains of positive and negative symptoms, suggesting that their superiority for negative symptoms does not represent a “core component of atypicality.” As noted previously, all SGAs had fewer EPS than haloperidol, even when the latter was used in doses below 7.5 mg/day.9
When Leucht et al9
compared their results to those of other meta-analyses by Geddes et al, Davis et al, and the Cochrane Schizophrenia Group, 25-27
the effect sizes were generally comparable. All meta-analyses - analyzing similar data sets - found that amisulpride, clozapine, olanzapine, and risperidone were significantly more efficacious than FGAs.
When Leucht and colleagues14
reviewed the head-tohead comparisons of SGAs they reported a similar pattern. Regarding total PANSS score change, olanzapine was more efficacious than aripiprazole, quetiapine, risperidone, and ziprasidone; risperidone was more efficacious than quetiapine and ziprasidone, and amisulpride was not statistically different from olanzapine or risperidone. However, regarding dropouts due to inefficacy, olanzapine was only superior to quetiapine and ziprasidone, two SGAs often dosed inappropriately low in schizophrenia, and amisulpride was more efficacious than ziprasidone. Surprisingly, clozapine only proved to be superior to zotepine and to risperidone in dropouts due to inefficacy. As the authors suggest, possibly inadequate doses of clozapine used in some studies might have contributed to these findings, which are inconsistent with most of the large individual studies.
In comparing these analyses to the results of CATIE and CUtLASS, there are some consistencies. In CATIE,17
olanzapine was superior in dropout rates due to inefficacy and time on effective treatment (at least when including the 23% of patients who were rerandomized to olanzapine), and clozapine (though given openly) was superior to all other studied SGAs in phase 2.28
clozapine was superior to other SGAs as well, but in this study, quality of life, and not all-cause discontinuation, was the primary outcome measure. This difference highlights the importance of the choice of the primary outcome measure, particularly in effectiveness studies, where the outcome is supposed to address elements of efficacy, tolerability, patient acceptability, and functioning.
Although the meta-analyses tended to find more support for risperidone's superiority than CATIE did, the dose equivalences used in CATIE have been challenged where the modal dose of risperidone was only 3.9 mg/day.
However, there were no differences between the individually studied SGAs and the FGA comparator perphenazine in CATIE,17
as well as between the class of clinician's choice SGAs and FGAs (mainly consisting of sulpiride, which some consider to be an SGA) in CUtLASS.23
The large effectiveness trials have been discussed in great detail elsewhere. Despite the rigorousness with which we try to design trials, there are always compromises in both design and execution that are unavoidable, particularly when multiple outcome measures are included and multiple questions are addressed simultaneously.
A particularly important issue which impacts all of the effectiveness trials was stressed by Kraemer et al.29
Whether a study is designed to establish superiority of one treatment or groups of treatments over others or to establish equivalence is critical. As Kraemer et al suggest, if a study is designed to demonstrate one treatment's superiority, then statistically nonsignificant results should not be assumed to be evidence of “equivalence.” To test this, a true noninferiority design is needed that generally requires larger samples.
The inevitable conclusions from these data are that drugs and drug classes are heterogeneous, and that we should not assume commonalities based on anything except appropriate comparisons. It is also obvious that every drug involves its own risks and benefits, and that clinicians have to evaluate data and make decisions based on the individual patients' presentation, history, sensitivities, preferences, responses, adverse effects, etc (Table I).
Considerations in choosing antipsychotic medications
This serves as a segue into the next section of this discussion, which focuses not so much on which drug to choose, but how to conceptualize and evaluate response (both therapeutic and adverse) in order to inform treatment decisions (which may or may not involve changing medication). It is our firm belief that the real challenges and opportunities in treating patients with schizophrenia lie in how treatments are managed, evaluated, and potentially altered, rather than which drug one chooses for an initial trial.
As with all treatment planning, formulating and tracking treatment goals and outcomes is important ().