Worth the Weight? Olanzapine Prescribing in Schizophrenia. A Review of Weight Gain and Other Cardiometabolic Side Effects of Olanzapine.

Abstract

About 80% of patients who experience a first episode of psychosis (FEP) will have another within 5 years (1). In a large meta-analysis of randomized controlled trials (RCTs), 12 months of antipsychotic treatment reduced the rate of relapse from 61 to 26% in FEP, and from 64 to 27% in chronic cases (2). Long-term antipsychotic treatment has been associated with a decrease in mortality rates, compared to untreated cases (3). However, compared to the general population, those with schizophrenia still die, on average, 14.5 years earlier (3, 4). Most life years lost relate to poor physical health outcomes—specifically mortality related to cardiovascular disease (CVD) (4). Adverse cardiometabolic side effects of antipsychotics, particularly second-generation antipsychotics (SGA), represent an undeniable contributor to the burden of cardiovascular morbidity and mortality amongst this cohort (5). Olanzapine, a SGA with one of the most significant cardiometabolic side effect profiles (5, 6), continues to be one of the most popular antipsychotics prescribed in schizophrenia (7–9). This commentary will consider some of the most pertinent research assessing the efficacy of olanzapine in schizophrenia management; suggest potential reasons for incongruence observed between guideline recommendations and prescribing practices; and finally, make suggestions as to how olanzapine-induced weight gain—a side effect that often represents the beginning of a series of escalating cardiometabolic derangements–can be recognized and its effects ameliorated. Olanzapine and Weight Gain Amongst those prescribed olanzapine early in psychosis management, 80% experience an increase of ≥7% of their baseline body weight (10, 11). With the exception of clozapine, whether short- or long-term anthropometric outcomes are being assessed, olanzapine is invariably listed as causing the most significant increases amongst users (6). This is not new information–the first review that aggregated data on weight changes following SGA use was published in 1999 (12). In a 2019 meta-analysis of 402 RCTs including data from 53,463 participants with multi-episode schizophrenia, olanzapine remained the antipsychotic most likely to induce clinically significant weight gain after clozapine and zotepine, the latter of which is not licensed in many countries (6). Antipsychotic-induced weight gain (AIWG) is a particularly important side effect, as it mediates cardiometabolic outcomes, including development of type 2 diabetes mellitus (T2DM) and subsequent CVD–the latter being responsible for approximately 60% of the excess mortality amongst those with schizophrenia previously highlighted (13). Aside from drastically reducing life expectancy, such high rates of physical comorbidity increases the personal, social and economic burden on mental illness across the lifespan. Significant weight gain may also influence outcomes related to mental health. AIWG is consistently listed as one of the most distressing side effects of antipsychotic treatment, frequently resulting in partial or complete antipsychotic non-adherence, and future reluctance to engage with treatment (14, 15). Furthermore, research is now emerging suggesting that obesity and metabolic syndrome may be independent predictors of relapse and re-hospitalization amongst those with a Severe Mental Illness (SMI) (16). Due to its significant association with weight gain and other cardiometabolic abnormalities, since 2009 several international guidelines in Europe, the United States, Australia and New Zealand have advised against olanzapine's use as part of first-line psychosis management (17). However, today olanzapine continues to be one of the most popular antipsychotics, extensively prescribed in both FEP and chronic cases, across the spectrum of illness severity and in many jurisdictions (7–9). Considering the cardiometabolic adverse effects of olanzapine are well-documented, what might be the reasons underlying its popularity? Does its prevalent use reflect poor translation of evidence and subsequent guideline recommendations into clinical practice? Or does its popularity reflect an “availability bias”, whereby clinicians ascribe greater efficacy to olanzapine compared to other antipsychotics, simply based on their more familiar and frequent use of olanzapine? It is worth first assessing efficacy data supporting olanzapine, both in symptom reduction and relapse prevention.