Switching Antipsychotic Medications to Reduce Adverse Event Burden in Schizophrenia: What Does the Literature Tell Us?
John W. Newcomer, MD; Peter J. Weiden, MD; and Robert W. Buchanan, MD
Listen to Audio Introduction
Weight gain and metabolic abnormalities associated with the use of antipsychotic medications can increase risk for cardiovascular disease, diabetes mellitus, and obesity-related cancers.1-5 Other problems associated with antipsychotics, such as extrapyramidal symptoms (EPS) and prolactin elevation, can interfere with quality of life and/or ability to function.1 These problems present a dilemma for physicians who commonly face clinical decisions regarding whether or not to switch a patient from one antipsychotic to another to achieve a potential reduction in these effects.
With the notable exception of clozapine for treatment-resistant patients, there does not appear to be convincing evidence for differential efficacy among available first-line antipsychotics for the treatment of core positive symptoms.1-6 Therefore, in selecting among first-line antipyschotics (i.e., antipsychotics other than clozapine), clinicians commonly consider the relative impact of the overall adverse event profile of each medication in relation to the preferences and vulnerabilities of individual patients. The objective of this project was to provide evidence-based guidance concerning when and how it may be appropriate to undertake elective changes in antipsychotic medications with the goal of reducing risk of adverse effects, particularly adverse effects associated with increased long-term health risks.
2009 Schizophrenia PORT Recommendations
This project builds on the results of the National Institute of Mental Health (NIMH)–funded 2009 Schizophrenia Patient Outcomes Research Team (PORT) pharmacologic treatment recommendations.1 PORT concluded that the available evidence (eg, number of appropriately designed studies) was insufficient to make a recommendation concerning switching antipsychotics because of persistent problems with weight gain; EPS, including tardive dyskinesia; or prolactin elevation. PORT acknowledged that switching antipsychotics can lead to a reduction in a number of adverse effects, including weight gain and elevated prolactin levels.7 However, they concluded that, to develop a treatment recommendation in this area, evidence was required that the majority of individuals would experience significant improvement in these areas (eg, weight gain, lipid abnormalities) without clinical deterioration.1,7 PORT indicated that they expected the results of the Comparison of Antipsychotics for Metabolic Problems (CAMP) study8 (ongoing at that time) and other future studies to help clarify this issue.
Literature Review Methodology
To address this question raised by PORT, the literature on switching antipsychotics was reviewed, with a focus on studies published since the 2009 PORT treatment recommendations. PubMed was searched using the terms antipsychotics, switching, randomized, and clinical trials. Of the 121 articles identified, 76 were excluded because they were review articles, dealt with changes of antipsychotics for acute symptoms (eg, agitation), or involved disorders other than schizophrenia (eg, bipolar disorder, dementia). Reference lists in identified articles and unpublished posters were also consulted. Switching studies were limited to those dealing with oral antipsychotics; consideration of long-acting injectable agents was beyond the scope of this project. A final list of 45 studies was assembled.
Criteria for study selection. Case reports, case series, chart reviews, and open, observational studies provide uncontrolled evidence and are therefore generally useful only for "hypothesis generation." In contrast, controlled experimental studies, including gold-standard prospective randomized controlled trials (RCTs), are designed to address specific questions for the purpose of "hypothesis testing." The majority of recent switching studies have focused on weight and metabolic outcomes, since these results have the greatest potential for significant clinical and public health impact.
The rest of this report briefly summarizes key findings from the literature in this area. For complete results on the literature review, please refer to the full publication of the results.9
Randomized Controlled Trials (Category 1)
Double-blind studies. In 2008, Newcomer et al10 published the results of the first double-blind RCT that examined switching to address undesirable body weight and lipid profiles. This was the only RCT on this question available to PORT.
Significantly more participants who switched to aripiprazole (11.1%) than stayed on olanzapine (2.6%) had clinically relevant (≥ 7%) weight loss. Although there was a statistically significant advantage in endpoint scores for stayers versus switchers (3.09 vs 3.74, P < .001), and more switchers versus stayers discontinued treatment (36% vs 26%), the mean Clinical Global Improvement scale scores for both groups were in the range of “no change” to "minimal improvement."
The double-blind, randomized CAMP study, published by Stroup et al8 in 2011, evaluated change in non–high-density lipoprotein (non-HDL) cholesterol and the efficacy of switching to aripiprazole versus staying on the current agent. Participants with schizophrenia or schizoaffective disorder with a body mass index (BMI) ≥ 27 and a non-HDL cholesterol level ≥ 130 mg/dL who were receiving a stable dose of olanzapine, quetiapine, or risperidone were randomly assigned to switch to aripiprazole (n = 109) or stay on their current medication (n = 106) for 24 weeks.
The small weight loss among stayers, in contrast to the persistent weight gain seen in the Newcomer et al10 study, may be related to the behavioral exercise and diet intervention all study participants received. As in Newcomer and colleagues’ study, beneficial changes in lipids occurred quickly (eg, over the first month), whereas weight changes were more gradual. As reported in other studies,10,11 a significantly higher percentage (44%) of switchers than stayers (25%) discontinued the medication before the end of the study. However, differences in serious adverse events and number of hospitalizations between the 2 groups were small.
The CAMP results8 make it possible to generalize from the Newcomer et al10 results, since the CAMP study found similar results for people switching from a variety of different agents.
Other randomized studies. Most of the other recent category 1 studies, while randomized and controlled, were not double-blind. Thus, while they provide useful supportive findings concerning reductions in parameters such as weight, EPS, and lipid and prolactin levels, it is not possible to rule out effects related to patient or investigator bias because of the open-label nature of the studies. In a randomized, open-label study, Kinon et al12 reported a reduction in prolactin levels and improvement in sexual functioning in participants switched from a first-generation antipsychotic (FGA) or risperidone to olanzapine (n = 27) compared with those who stayed on an FGA (n = 9) or risperidone (n = 18). Cortese et al13 found improvement in EPS (ie, parkinsonism, akathisia, and dyskinesia) in participants randomly assigned to switch from olanzapine, risperidone, or an FGA to quetiapine (n = 13) compared to those who continued on the previous antipsychotic (n = 9). Chen et al14 reported statistically significant improvements in weight, BMI, and triglyceride and HDL levels in participants randomly assigned to switch to aripiprazole (n = 24) or ziprasidone (n = 28) from other antipsychotics.
Summary. Evidence from category 1 studies, in particular the Newcomer et al10 and Stroup et al8 studies, indicates that switching to a low metabolic risk antipsychotic under controlled conditions can produce benefits in both weight/BMI and lipid profile without significant risk of clinical deterioration. Randomized controlled open-label studies also suggest benefits of switching medications because of EPS or elevated prolactin levels. One caveat in interpreting these results is that people treated with clozapine were excluded from these studies, so that the relative safety of switching from clozapine for metabolic reasons remains understudied but associated with higher risk for clinical worsening in the few studies concerning clozapine switching to date.15,16
Randomized Trials Not Specifically Designed as Switching Studies (Category 2)
The majority of studies in category 2 involved secondary analyses of data from the NIMH-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study,6 which enrolled approximately 1,500 people with schizophrenia (the 3 newest antipsychotics, asenapine, iloperidone, and lurasidone, were not included in CATIE or the PORT deliberations). CATIE is the largest practical clinical trial conducted to evaluate antipsychotic efficacy. The CATIE study did not support differences in efficacy among antipsychotics other than clozapine, but did find marked variability in adverse effect profiles. Several analyses of CATIE data have addressed relevant switching questions.
Several other category 2 studies addressed relevant questions. Based on a 1-year randomized open-label cost-effectiveness study, Faries et al20 reported poorer clinical and economic outcomes (ie, more frequent and rapid use of acute care services) among switchers (n = 191) than among stayers (n = 460) and improvements in clinical outcomes, but more weight gain, among those who switched from risperidone to olanzapine than among those treated with risperidone.21
Stahl et al22 reported results from a 6-month open-label extension of the Program to Evaluate the Antipsychotic Response to Lurasidone (PEARL 2) randomized, placebo-controlled, double-blind study, a large multicenter trial evaluating the efficacy of 40 and 120 mg/d of lurasidone versus placebo or olanzapine 15 mg/d. Participants who completed 6 weeks of double-blind treatment with lurasidone, olanzapine, or placebo were eligible to continue treatment with lurasidone for up to 6 months (44.5% [113/254] completed 6 months). In this continuation phase, participants previously treated with olanzapine experienced decreases in weight (mean reduction of 1.8 kg) and lipid levels while efficacy was maintained. Participants previously treated with placebo or lurasidone had minimal changes in these parameters.
Summary. Evidence from category 2 studies generally supports the observation from category 1 studies8,10 that switching from antipsychotics with higher metabolic risk to those with lower risk under controlled conditions can produce metabolic and weight benefits without significant risk of clinical deterioration. However, studies also confirmed that participants switched to a new antipsychotic are more likely to discontinue treatment than those who remain on the same agent, highlighting the need to optimize current treatment and perform a risk-benefit assessment before switching to a new agent.
Uncontrolled and/or Open-Label Trials (Category 3)
Switching methods. Of the 16 studies in category 3, the majority examined strategies for switching from one medication to another (ie, stopping the first agent before starting the new medication, maintaining a therapeutic dose of the first medication while titrating up to a therapeutic dose of the new medication, or gradually discontinuing the first medication while titrating the new medication to a therapeutic dose). In general, these studies found few differences in outcomes among the strategies, although there was some evidence favoring more gradual discontinuation of the first antipsychotic to minimize problems early in the switching process.23-27
As an example, 2 recent studies supported this finding. In a 6-week, multicenter, randomized, open-label study in which 240 stable participants were switched from other antipsychotics to lurasidone because of insufficient efficacy or safety/tolerability concerns, McEvoy et al27 used a gradual discontinuation strategy to taper participants off their initial antipsychotic and 3 different strategies to titrate lurasidone. The first medication was tapered by 50% by day 7 and discontinued by day 14, with participants randomly assigned to 1 of 3 methods of starting lurasidone: 40 mg/d for 2 weeks, 80 mg/d for 2 weeks, and 40 mg/d for week 1 and 80 mg/d for week 2. After 6 weeks, participants were successfully switched regardless of method of starting the new medication.
Data from another recent 12-week, randomized, multicenter, open-label switching study,26-28 in which participants were switched from olanzapine (n = 155), risperidone (n = 175), or aripiprazole (n = 170) to iloperidone, showed that more participants in the group who were switched abruptly rather than gradually discontinued due to adverse events. The difference in discontinuations was primarily due to dizziness associated with α1 antagonism during the first 1–2 weeks of iloperidone treatment, which decreased over time.
Switching due to adverse effects. Data from open-label uncontrolled studies concerning changes in weight, metabolic parameters, and other side effects after switching antipsychotics are generally consistent with findings from controlled trials.26-32 The following sections briefly review findings from more recent studies in this area.
Weight gain and/or metabolic abnormalities. In 3 long-term, open-label extension studies in which participants switched from risperidone (n = 43), olanzapine (n = 71), or an FGA (n = 71) to ziprasidone and could continue ziprasidone for up to 58 weeks,31 clinically significant and sustained reductions in weight, BMI, and total cholesterol and triglyceride levels were observed in those who switched from risperidone or olanzapine to ziprasidone.
In the McEvoy et al27 6-week study discussed earlier, subjects switched to lurasidone showed mean decreases in weight and improvements in metabolic parameters.
Prolactin elevation. Byerly et al32 found that elevated prolactin levels in participants treated with risperidone decreased significantly and returned to normal 1 week after switching to aripiprazole, with this change maintained for the 8 weeks of the study.
Sedation. The McEvoy et al27 switching study provided useful information on switching from more to less sedating agents.
Summary. Data from the open-label, uncontrolled category 3 studies generally confirm and extend findings from the category 1 and 2 studies. A majority of category 3 studies examined switching methods, with a number supporting more gradual discontinuation of the first agent to minimize problems early in the switching process, particularly when starting an agent that requires gradual titration (eg, iloperidone, due to hypotension related to α1 antagonism). Studies in all 3 categories suggest that the magnitude of change in parameters such as weight, lipids, prolactin, and EPS can vary substantially depending on the specific agents involved in the switch. Thus, the greatest reduction in weight would be expected when switching from olanzapine to an agent with low liability for weight gain, the greatest reduction in EPS or prolactin would be expected when switching from an FGA or risperidone, and the greatest changes in sedation would be expected when switching from a more sedating (olanzapine or quetiapine) to a less sedating agent.
Part 2 of this online series will present clinical recommendations based on the evidence reviewed here.
- Buchanan RW, Kreyenbuhl J, Kelly DL, et al. Schizophrenia Patient Outcomes Research Team (PORT). The 2009 Schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71–93. doi:10.1093/schbul/sbp116 PubMed
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- Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–1223. doi:10.1056/NEJMoa051688 PubMed
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- Stroup TS, McEvoy JP, Ring KD, et al. Schizophrenia Trials Network. A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: Comparison of Antipsychotics for Metabolic Problems (CAMP). Am J Psychiatry. 2011;168(9):947–956. doi:10.1176/appi.ajp.2011.10111609 PubMed
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- Byerly MJ, Marcus RN, Tran QV, et al. Effects of aripiprazole on prolactin levels in subjects with schizophrenia during cross-titration with risperidone or olanzapine: analysis of a randomized, open-label study. Schizophr Res. 2009;107(2–3):218–222. doi:10.1016/j.schres.2008.09.019 PubMed