Change in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics

Schizophrenia is a severe and lifelong mental illness characterized by impairment of most domains of cognitive functioning, often leading to functional disability [1]. Patients with schizophrenia suffer not only from symptoms such as delusions or hallucinations but also impaired occupational functioning and low levels of productivity (e.g., paid employment, being a student, or other useful activity) and high rates of unemployment [2‐4].

The poor productivity level among patients with schizophrenia has long been recognized as a core component of the burden of illness and its economic cost [5, 6]. The financial cost of schizophrenia in the United States in 2002 was estimated to be $62.7 billion [6]. In another study of the economic burden of schizophrenia in the United States in 2002, the indirect excess cost due to unemployment was found to be the largest component of the overall excess annual costs [7].

Improving patients' productivity level is an important goal in the treatment of schizophrenia and was previously identified as the most preferred treatment outcome, more than improvement of symptoms, by clinicians, patients, their families as well as public policy makers [8]. Rosenheck et al. (2005) [9] evaluated the personal outcome preferences of a large sample of patients treated for schizophrenia and identified work as the 4th preferred outcome among 6 assessed domains including social life, energy, symptoms, work, confusion and treatment-emergent adverse events. Importantly, several clinical guidelines [10‐12] cite supported employment programs as one of the most valuable psychosocial treatment interventions for schizophrenia.

Although little is known about predictors of productivity level in the treatment of patients with schizophrenia, the link between medication adherence or persistence and functional outcomes has been consistently shown [13‐15]. Adherence to antipsychotic treatment is associated with better long-term improvements in outcome measures including decreased risk of psychiatric hospitalizations, detentions, victimizations, substance use, and severity of alcohol-related issues, as well as improvements in mental health and satisfaction with social life in general [14]. In addition, longer treatment duration with antipsychotics (persistence) was found to be associated with improved symptom severity levels [16] and greater functional outcomes in the treatment of patients with schizophrenia [15]. Recent meta-analyses have shown that antipsychotics significantly differ on their pharmacology, efficacy, safety and tolerability profiles [17, 18]. The choice of antipsychotics may also play a significant role in patients' adherence to or persistence with antipsychotic medications, as adherence and persistence on antipsychotic medication appear to be highly intercorrelated [19]. Olanzapine treatment is associated with better persistence, or lower rates of medication discontinuation for any cause, compared to other antipsychotics [20‐24]. Moreover, few studies have suggested that this advantage may be due to the greater efficacy of olanzapine relative to other antipsychotics [21, 22]. However, it is unclear whether these differences have any impact on the patient's productivity level.

Taken together, productivity is a very important area in the treatment of schizophrenia and yet it is largely unstudied. To our knowledge, there has not been any systematic investigation on the comparative productivity among antipsychotic drugs. To address this question, we conducted a post hoc analysis of double-blind, active-controlled trials from Lilly clinical trial database comparing olanzapine with other antipsychotic drugs on change in level of productivity. The links between productivity and symptom severity and between productivity and patients' persistence on therapy were also investigated.

This is the first study to evaluate improvement in productivity among patients with schizophrenia treated with various antipsychotics. Using data from 6 randomized, double-blind clinical trials of antipsychotic therapy, this post hoc investigation detected significant differences between olanzapine and some of the studied antipsychotics on improvement in level of productivity. Change in level of productivity from baseline was significantly greater in both chronically ill and first episode patients with schizophrenia treated with olanzapine compared with some of the other antipsychotics. In chronically ill patients, olanzapine treatment was associated with significantly greater improvement in productivity levels compared to risperidone and ziprasidone, but not with quetiapine or aripiprazole. Higher rates of moderately high and high productivity levels at endpoint were also observed with olanzapine- compared to risperidone treatment. For first episode patients treated with olanzapine, significantly higher rates of moderately high and high productivity at endpoint were observed during the acute phase and the long-term treatment phase compared to haloperidol-treated patients.

Current findings are consistent with those reported in a randomized, open label, flexible dose, multi-center study of outpatients with schizophrenia who were assigned to a 1-year treatment with olanzapine or risperidone [33]. In that study, the greatest treatment group difference was found on the occupational/employment outcome measure (p = 0.0024). The present findings are, however, inconsistent with two other schizophrenia studies in which the olanzapine- and risperidone-treated patients did not significantly differ on employment outcomes [34] or job skills learning [35]. This inconsistency may be related to methodological differences and especially to differences in the definition of productivity. For example, we used an ordinal measure of productivity, which encompassed work for pay as well as useful non-paid activity such as volunteer work or being a student, thus possibly being more sensitive to change than the dichotomous measure (i.e., working for pay vs. not working) used previously [33].

We also found significant associations between productivity level and improvement in symptom severity levels among chronically ill and first episode patients. These findings are consistent with previous schizophrenia research in which symptom improvement and symptom remission were shown to be associated with better functional outcomes [36‐39]. While our study found significant associations between productivity level and disorganized thinking, positive symptoms and negative symptoms, previous research has shown that negative symptoms have a more robust link to functional outcomes, with lower PANSS negative symptoms being able to predict functional remission [36] and paid employment [40‐43]. Conversely, poorer employment and occupational functioning were previously found to be strongly predicted by severe negative symptoms [40, 42, 43].

Our analysis also found significant associations between productivity level and persistence on therapy, defined as study completion. In each of the 6 trials, which ranged between 12 (for acute phase) and 28 weeks in duration, the completers had significantly greater improvement in productivity level than patients who dropped out of the study. These results are consistent with previous studies showing that longer duration of antipsychotic treatment is correlated with better functional outcomes, including better occupational functioning, among patients with schizophrenia [15].

The current study found an advantage for olanzapine therapy on improving productively level compared to treatment with risperidone, ziprasidone, and haloperidol, but not when compared with quetiapine and aripiprazole. Although our post hoc exploratory analysis cannot clarify the underlying drivers of the current results, the findings can be explained using the link previously shown between longer treatment duration and better clinical efficacy in the treatment of patients with schizophrenia [21, 22, 44‐46]. In meta-analytical studies of antipsychotic therapy for schizophrenia, which incorporated data from numerous randomized clinical trials, olanzapine was found to confer greater efficacy compared to haloperidol [17] risperidone and ziprasidone [18]. Furthermore, patients treated with olanzapine were consistently found to stay longer on treatment compared to those treated with haloperidol [23, 31, 44‐49], risperidone [21, 23, 24, 28, 48‐56] and ziprasidone [21, 27, 57‐59]. Thus, antipsychotic treatment choice may influence patients' improvement in symptom severity, their treatment duration and their functional outcomes as measured, in this study, by productivity levels.

This study possesses several limitations. First, this is a post hoc analysis of 6 randomized, double-blind clinical trials composed of chronically ill patients with schizophrenia and first episode schizophrenic patients studied over different treatment durations [between 12 (for acute phase) and 28 weeks]. The current findings will require replication in studies assessing these outcomes in an a priori manner. Second, the current analysis was conducted in randomized clinical trials, thus it is unclear if the findings may generalize to schizophrenia patients treated in usual care settings. Lastly, as this research is the first to systematically investigate the productivity levels in treatment of schizophrenia, patients' productivity level was assessed with a single item with 5 response options and the reliability and validity of this productivity measure has not been established yet.

Current findings suggest that antipsychotic medications may significantly differ on beneficial impact on productivity level in the treatment of patients with schizophrenia, and highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy. This post hoc analysis suggests an advantage for olanzapine therapy over several other antipsychotics on improving productivity levels among chronically ill and first episode patients with schizophrenia. This finding will require replication in future research.