This study compared olanzapine and risperidone on the risk of psychiatric hospitalization for patients with schizophrenia who were treated in usual care settings. Current findings complement prior findings from clinical trial research, thus providing clinicians and mental health decision makers with information to help guide their resource allocation decisions at a time of growing budgetary constraints in the mental health care delivery system. Specifically, this study was intended to investigate in usual care settings whether the two most widely used second-generation antipsychotics, olanzapine and risperidone, differ in a meaningful fashion on the risk of psychiatric hospitalization, the costliest of all service components in the treatment of patients with schizophrenia. Our findings demonstrated that compared to risperidone-treated patients, the olanzapine treatment group had a clinically meaningful and a statistically significant lower rate of hospitalization and fewer hospitalized days during the year following initiation. We found a mean group difference in days hospitalized translated to $2,502 in psychiatric hospitalization cost savings per olanzapine-treated patient per year, on the average. These cost savings more than offset the higher annual acquisition cost of olanzapine and can help maintain more patients in the community. If psychiatric hospitalization is to be viewed as a marker or a proxy for effectiveness [16
], the current findings suggest that olanzapine should be a preferred therapeutic option since patients receiving olanzapine may require less psychiatric inpatient care. In addition to having economic implications, the current findings are clinically meaningful to treatment providers, to patients, and to patients' relatives because inpatient hospitalizations cause a substantial societal burden, including personal suffering, disruption of peoples' lives, and interruptions of patients' mental health treatments in the community.
Our findings documented the consistency with which treatment with olanzapine was associated with a lower risk of hospitalization as indicated by lower rates of hospitalization, shorter total hospitalization time, and a longer time to first hospitalization. It is noteworthy that findings were consistent with results from the sensitivity analysis using intent-to-treat approach in which the risperidone-treated patients had a numerically higher hospitalization rate, a longer hospitalized duration, and a shorter median time to first hospitalization. Overall, the findings provide a cohesive picture in which the olanzapine-treated patients were not only hospitalized at a lower rate and for fewer days, but their median time to hospitalization was longer than that for patients treated with risperidone. Longer stay in the community, as observed with olanzapine, may provide the patients and their treatment teams with greater opportunities to pursue psychosocial and vocational rehabilitation and to improve the therapeutic alliance, all of which are linked to better long-term prognosis [24
The current findings are consistent with two previous randomized double-blind clinical studies of olanzapine and risperidone in the treatment of schizophrenia [12
]. Interestingly, at the end of the first study, which was 6-months long, the olanzapine-treated group was hospitalized for 3.6 fewer days than the risperidone-treated patients, and at 6-months in the current study the group difference was almost identical, with 3.9 fewer hospitalization days for the olanzapine than the risperidone treatment group. Our findings are similarly consistent with those found in another randomized double-blind study of patients with schizophrenia [13
] in which olanzapine-treated patients had a significantly lower rate of psychiatric hospitalization than patients treated with risperidone in the year post initiation. The lower risk of hospitalization in that study was also translated into meaningful cost savings for the olanzapine-treated patients [24
At present, there are no published findings from any head to head double-blind controlled studies of olanzapine versus risperidone demonstrating that risperidone-treated patients have a lower or even a comparable risk of hospitalization compared with patients treated with olanzapine. There is, however, a growing body of retrospective studies using intent-to-treat (ITT) methodology, comparing olanzapine and risperidone on the risk of hospitalization [6
]. These studies provided a mixed picture and reported either a lower risk of hospitalization for olanzapine than for risperidone-treated patients [30
], fewer hospitalizations for risperidone-treated patients [32
], or similar rates of psychiatric hospitalization for olanzapine and risperidone-treated patients [6
Unlike previous ITT retrospective studies, the current study aimed to avoid the potential pitfalls associated with an ITT methodology. As we have demonstrated, the bias can be introduced when there are changes in patients' medication regimens, a frequent phenomenon in the dynamic and complex treatment of patients with schizophrenia [37
Our findings may help clinicians in choosing between olanzapine and risperidone or assist decision makers when considering the need to maintain open and unrestricted formulary access to olanzapine. Decision makers will need to balance the higher price of olanzapine compared with risperidone and the cost savings attributed to reduced psychiatric hospitalization. While we aimed to minimize potential economic bias from the payer perspective, the inclusion of patients who were continuously treated with the index antipsychotic drug during the study period also provided for a more optimal comparison between the two treatment groups by attempting to level the potentially confounding impact of non-adherence with medication, the best predictor of future psychiatric hospitalization. Furthermore, the exclusion of the non-adherent group can be construed as a more conservative approach and also as "raising of the effectiveness bar" because compared to olanzapine, the risperidone-treated patients were previously shown to have a significantly shorter time to all-cause drug discontinuation [33
In this study, the two treatment groups were continuously treated with the index antipsychotic drug during the year following initiation. Based on patients' self-reports of medication adherence the treatment groups were assumed to be comparable on adherence with medication regimens. If one accepts the comparability of the two groups on adherence with medication, then the observed differences on psychiatric hospitalization parameters between the olanzapine and the risperidone-treated groups are likely to reflect differences in the effectiveness of the two antipsychotics. Based on prior research [3
], about 40% of schizophrenia patients' hospitalizations are attributable to medication non-adherence whereas about 60% is due to medication efficacy factors. Differential efficacy between olanzapine and risperidone was previously demonstrated in randomized controlled trials of patients with schizophrenia, such that olanzapine therapy was found to provide patients with a more robust therapeutic response [13
], particularly in the treatment of negative symptoms [13
]. A significantly greater proportion of olanzapine-treated patients were found to achieve 20%, 40%, and 50% improvement on a general measure of psychopathology and on specific measures of negative symptoms. The differential efficacy found in randomized controlled trials was replicated in a recent naturalistic study [42
] in which treatment with olanzapine provided patients with a greater improvement on negative symptoms than treatment with risperidone. Importantly, negative symptoms, such as apathy, poverty of speech, and lack of motivation are part of the schizophrenia syndrome and their presence was found to predict a longer duration of psychiatric hospitalization [43
Results of the current study need to be evaluated in the context of their limitations. First, this study was a non-randomized observational study in which potential selection bias, particularly due to differences in illness severity, could not be ruled out because information about patients' clinical status was unavailable at the time of initiation on the index drug. Further, the comparability of the treatment groups on adherence with medication regimens was based on prescription and self-report data, which may not reflect patients' medication adherence in an accurate fashion. However, previous research [44
] has demonstrated a very high concordance rate between the presence of a prescription for psychotropic medications such as an antipsychotic, and the fill of the prescription in a patient population that resembles SCAP participants (severely mentally ill patients, diagnosed primarily with schizophrenia, covered by Medicaid). Another limitation is the generalizability of the findings due to the inclusion of participants who continued on the index antipsychotic for at least 1 year. This inclusion criterion reduced by one half the number of participants eligible for the current analysis. Consequently, results may not generalize to patient treated with olanzapine or risperidone who discontinued the index drug regimen prior to the end of the first year. In addition, results may not generalize to patients treated in the private sector because public payers covered almost all SCAP participants.
In conclusion, results of our naturalistic study are consistent with prior clinical trial research, demonstrating that among treatment-adherent patients olanzapine conferred a lower risk of psychiatric hospitalization than risperidone, thus reducing the costliest service component in the treatment of schizophrenia. Although olanzapine therapy was found to have a lower hospitalization risk than treatment with risperidone on each of the three studied hospitalization parameters, there is a need to replicate the current findings in other clinical care settings. Optimally, future comparative studies would incorporate assessments at the time of initiation on the index drug, use direct measures of medication adherence, and recognize that an intent-to-treat methodology may obscure the true economic impact of the studied antipsychotic drugs.