Switching Antipsychotic Medications to Reduce Adverse Event Burden in Schizophrenia: Evidence-Based Clinical Recommendations

John W. Newcomer, MD; Peter J. Weiden, MD; and Robert W. Buchanan, MD

As recently noted by Murad and Montori,1 clinicians should use the totality of available evidence when making clinical decisions with their patients, preferentially weighing evidence from randomized controlled trials (RCTs—the gold standard), but also incorporating clinical observations from case reports, case series, uncontrolled observational studies, and relevant expert opinion. This report presents clinical recommendations based on our review of the available evidence and addresses key questions about switching antipsychotics left open by the 2009 Schizophrenia Patient Outcomes Research Team (PORT) pharmacologic treatment recommendations.2 (For details on the methods and results of literature review, please refer to the first online report in this series and to the full publication of the results.3)

Can Switching Antipsychotic Medications Produce Improvements in Weight and Lipid Parameters, EPS, or Prolactin Levels Without Destabilizing Patients?

Results of studies published since the 2009 PORT treatment recommendations2 strongly support that switching patients from higher to lower metabolic risk antipsychotics can help to improve adverse weight and lipid profiles associated with the prior antipsychotic treatment. In addition, these studies show that, with appropriate clinical monitoring, switching antipsychotics is relatively safe and unlikely to cause significant clinical deterioration.4,5 One important caveat concerning these results is that people treated with clozapine were excluded from the studies on which these conclusions were based, so that the relative safety of switching from clozapine for metabolic reasons remains understudied but associated with a higher risk for clinical worsening in the few studies to date that have examined switches involving clozapine.15,16

The weight and lipid benefits of switching are clearest for switches from agents with high metabolic risk, such as olanzapine, to those with lower propensity for weight gain or dyslipidemia, such as aripiprazole, ziprasidone, and lurasidone. Evidence, although not as strong, also exists concerning improvements that may be achieved by switching to improve other adverse effects, including extrapyramidal symptoms (EPS) and prolactin elevation. Although assessment of the risk of clinical worsening of switching was not as rigorous in studies that evaluated EPS and prolactin, a number of studies4-19 using different experimental and analytic designs now support that antipsychotic switches (with the exception of switches from clozapine) are associated with only modest risk of clinical worsening that can be best managed by gradual discontinuation of the prior antipsychotic.

The information in the following sections on relative risks of common problems associated with antipsychotics is based on a recent meta-analysis20 of data from 212 RCTs concerning 15 antipsychotic medications and other evidence in the literature.

Switching because of weight and/or lipid abnormalities. The greatest amount of evidence supports switching antipsychotic medications to target excessive weight gain and lipid abnormalities. Available studies indicate that such switches can result in improvements in these parameters without a significant risk of destabilization. The relative risk of weight gain is olanzapine > clozapine >> iloperidone > low-potency first-generation antipsychotics (FGAs) > quetiapine > risperidone = paliperidone > asenapine > high-potency FGAs = aripiprazole = lurasidone = ziprasidone.2,20,21

Switching because of EPS. The relative risk of EPS among the antipsychotics is high-potency FGAs > mid-potency FGAs = risperidone = paliperidone > low-potency FGAs > lurasidone = asenapine = ziprasidone > aripiprazole > olanzapine > iloperidone = quetiapine > clozapine.2,20,22,23 Less evidence is available concerning switching in this area, but reductions in EPS have been reported when patients were switched to quetiapine10 or ziprasidone.7

Switching because of elevated prolactin levels. The greatest risk of elevated prolactin levels is associated with risperidone and paliperidone followed by high-potency FGAs; most of the other available antipsychotics are associated with a smaller risk of elevated prolactin levels, while quetiapine and aripiprazole have been found to be associated with less elevation in prolactin levels than placebo.2,20 A randomized, controlled, open-label trial9 reported reductions in prolactin levels when participants were switched from an FGA or risperidone to olanzapine. Two uncontrolled studies also reported reductions in prolactin levels when participants were switched from an FGA or risperidone to ziprasidone7 and from olanzapine or risperidone to aripiprazole.19

Deciding on an Elective Change of Antipsychotic Medication

Physicians, patients, and families may place different value on various outcomes, which highlights the need for personalized medicine, shared decision-making, and patient-centered care. For example, while a reduction in symptom severity may be a critical concern for one individual, reduction in sedation or weight gain may be a more pressing concern for another. Clinicians also need to help patients understand and manage the concept of future risk (eg, potential long-term effects of obesity and metabolic abnormalities).

AV 1. Steps in Deciding to Make an Antipsychotic Switch (00:45)


Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study24 and other studies4,5,12 indicate that individuals who switch to a new medication are more likely to discontinue treatment (eg, return to prior medication) compared to those who do not switch, presumably due to the challenges of adjusting to a new medication. Therefore, Essock et al24 recommended first optimizing the current treatment regimen before considering a switch.

Options to consider before switching. If a patient has achieved a satisfactory symptomatic response but has developed clinically significant treatment-related adverse events (eg, excessive weight gain, dyslipidemia) that make it difficult to continue taking the medication or that pose long-term health risks, the risk-benefit analysis may be complex.

AV 2. Options to Consider With the Patient Before Switching Antipsychotics (00:45)


Optimization/dose adjustment. When a patient treated with an antipsychotic experiences a serious problem that interferes with quality of life or ability to function or poses long-term health risks, consider whether a dose adjustment might reduce the problem while maintaining efficacy. Of course, this will help only if the problem is dose dependent. For example, EPS, sedation, amenorrhea, agitation, and activation may respond to dose adjustment (eg, lowering the dose for early activation with aripiprazole, raising the dose for early activation with ziprasidone), while other effects, such as weight gain, are generally not dose dependent within the usual dose ranges used to treat schizophrenia.25

Adjunctive interventions. Adjunctive medications can be considered to treat problems, such as early activation or insomnia (eg, benzodiazepines), EPS (eg, anticholinergic agents, β-blockers), obesity (eg, weight-loss agents recently approved by the US Food and Drug Administration, although none has been tested or approved in people with schizophrenia or for treatment or prevention of antipsychotic-induced weight gain), dyslipidemia (eg, statins), or elevated prolactin levels (eg, bromocriptine). Concerns about use of adjunctive agents include adverse effects associated with adding a second medication (eg, cognitive deficits with anticholinergic medications), limited evidence of efficacy, and potential for drug interactions.

Switching to a different antipsychotic medication to reduce or minimize adverse effects. After determining that the adverse effect in question is likely to be amenable to a change in medications, a risk-benefit assessment of switching antipsychotic medications should be conducted with the patient.

Implementing the Switch

Selecting the next antipsychotic medication. In deciding with the patient on the most appropriate medication to switch to and educating the patient about what to expect, consider the pharmacodynamic and pharmacokinetic profiles of both medications involved in the switch.

AV 3. Common Adverse Effects Associated With Receptor Blockade (01:02)


Making a switching plan. Although studies have generally found no ultimate difference in outcomes for different switching strategies, results of switching studies support more gradual cross-titrations as being likely to reduce dropout and rebound adverse effects.14-17 The clinician should develop a plan for completely discontinuing the first medication and reaching a therapeutic dose of the new agent and educate patients about potential withdrawal problems.

Monitoring for problems during the switch. The most common problems that complicate switching are insomnia, sedation, and anxiety. Sleep disturbances may represent rebound effects from discontinuing a more sedating drug or they may reflect the less sedating effect of the new agent. Switches implemented to address weight and metabolic problems usually involve changing from a drug with more potent antihistaminic and hence sedating properties (eg, olanzapine) to a less sedating agent, so that insomnia may occur early during the transition. McEvoy et al18 found lower rates of study completion in participants switching from more sedating agents to lurasidone. Although these problems are usually transient (ie, no more than 2 weeks), clinicians should educate patients and families about the possibility and provide short-term sedatives if needed to facilitate a successful switch. When switching from a drug with more potent to one with less potent D2 blockade (eg, from risperidone to quetiapine), short-term withdrawal dyskinesias may occur that should be distinguished from effects of the new medication. When switching to a medication with significant α1-adrenergic antagonism (eg, iloperidone), patients should be educated about the potential for early dizziness.26 When switching from more potent anticholinergic regimens (eg, olanzapine or in the setting of adjunctive benztropine prescribed for EPS), muscarinic antagonism should be decreased gradually (eg, over 1–2 weeks) to minimize anticholinergic withdrawal symptoms.

Monitoring outcomes. When switching because of safety issues, continue to focus on efficacy, since even if the safety/tolerability profile of the new drug is more acceptable, a relative loss of efficacy will limit the success of the switch. One cannot be sure about the relative effectiveness of the new medication until the individual has been on a full therapeutic dose of monotherapy for at least 4 weeks, and it may not be possible to evaluate the ultimate effectiveness of the new agent until some months have passed.

In monitoring the problems that led to the switch, one should keep in mind that changes occur over varying periods of time. Thus, there may be very rapid improvement associated with cessation of pharmacodynamic effects (eg, anticholinergic effects, prolactin elevation). Byerly et al19 found that prolactin levels returned to normal within 1 week after patients were switched from risperidone to aripiprazole. Improvements in lipids and other metabolic parameters are also likely to occur relatively rapidly (eg, 4–8 weeks), while changes in body weight are generally more gradual.4,5 Continued reduction in weight may occur for up to a year or longer.6-8

AV 4. Steps in Implementing an Elective Antipsychotic Switch (00:57)


Special problems in switching from clozapine. The limited research in this area27,28 indicates that switching someone from clozapine to another antipsychotic should be done very cautiously if at all, carefully weighing potential pros and serious potential cons, including especially the risk of withdrawal effects, destabilization, and relapse. However, such a switch may have to be very cautiously considered for individuals who have not achieved any satisfactory response to clozapine or for those who are experiencing intolerable adverse effects.

Careful methodology is especially important in switching from clozapine. It has very strong anticholinergic properties, and patients tapered off clozapine often experience anticholinergic rebound phenomena, especially when clozapine is discontinued abruptly. Using an adjunctive anticholinergic agent (eg, benztropine) while slowly lowering the dose of clozapine may help diminish this rebound effect. Antihistaminic and α-adrenergic rebound symptoms may also occur when a person is tapered off clozapine.


The goal of this project was to provide updated guidance regarding management of adverse effects via elective changes in oral antipsychotic medications in the treatment of schizophrenia. The 2009 PORT treatment recommendations2 acknowledged that there was evidence that switching antipsychotics can lead to an improvement in a number of parameters, including weight gain and elevated prolactin levels. However, the authors at that time concluded that they could not make a recommendation in these areas without further evidence regarding the safety of the practice. The current report examined published evidence that is now available concerning switching antipsychotic medications. Two RCTs, 1 available to the PORT4 and 1 published since that time,5 support the recommendation that switching from higher to lower metabolic risk antipsychotics can produce weight and lipid benefits without a significant risk of clinical deterioration. Secondary analyses of data from the CATIE study have further established that switching to a medication with lower liability for weight and metabolic abnormalities is unlikely to result in significant loss of clinical benefit.12,29 On the basis of the totality of available evidence, including well-established population-based evidence that reductions in body weight and other metabolic risk factors are strongly associated with reductions in risk for cardiovascular disease and diabetes, clinicians should individually consider patient risk and opportunities for risk reduction that can be afforded by judicious switching from higher risk to lower risk antipsychotics. Evidence also supports the use of switching to address clinical problems such as EPS and prolactin elevation. Adverse event management during chronic antipsychotic therapy is an area in which tolerability, personalized medicine, shared decision-making, and patient-centered care will remain crucial.

  1. Murad MH, Montori VM. Synthesizing evidence: shifting the focus from individual studies to the body of evidence. JAMA. 2013;309(21):2217–2218. doi:10.1001/jama.2013.5616 PubMed
  2. 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
  3. Newcomer JW, Weiden PJ, Buchanan RW. Switching antipsychotic medications to reduce adverse event burden in schizophrenia: establishing evidence-based practice [ACADEMIC HIGHLIGHTS]. J Clin Psychiatry. 2013;74(11):1108–1120. doi:10.4088/JCP.12028ah1 PubMed
  4. Newcomer JW, Campos JA, Marcus RN, et al. A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine. J Clin Psychiatry. 2008;69(7):1046–1056. doi:10.4088/JCP.v69n0702 PubMed
  5. 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
  6. Weiden PJ, Simpson GM, Potkin SG, et al. Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. J Clin Psychiatry. 2003;64(5):580–588. doi:10.4088/JCP.v64n0514 PubMed
  7. Weiden PJ, Daniel DG, Simpson G, et al. Improvement in indices of health status in outpatients with schizophrenia switched to ziprasidone. J Clin Psychopharmacol. 2003;23(6):595–600. doi:10.1097/ PubMed
  8. Weiden PJ, Newcomer JW, Loebel AD, et al. Long-term changes in weight and plasma lipids during maintenance treatment with ziprasidone. Neuropsychopharmacology. 2008;33(5):985–994. doi:10.1038/sj.npp.1301482 PubMed
  9. Kinon BJ, Ahl J, Liu-Seifert H, et al. Improvement in hyperprolactinemia and reproductive comorbidities in patients with schizophrenia switched from conventional antipsychotics or risperidone to olanzapine. Psychoneuroendocrinology. 2006;31(5):577–588. doi:10.1016/j.psyneuen.2005.12.006 PubMed
  10. Cortese L, Caligiuri MP, Williams R, et al. Reduction in neuroleptic-induced movement disorders after a switch to quetiapine in patients with schizophrenia. J Clin Psychopharmacol. 2008;28(1):69–73. doi:10.1097/jcp.0b013e318160864f PubMed
  11. Chen Y, Bobo WV, Watts K, et al. Comparative effectiveness of switching antipsychotic drug treatment to aripiprazole or ziprasidone for improving metabolic profile and atherogenic dyslipidemia: a 12-month, prospective, open-label study. J Psychopharmacol. 2012;26(9):1201–1210. doi:10.1177/0269881111430748 PubMed
  12. Rosenheck RA, Davis S, Covell N, et al. Does switching to a new antipsychotic improve outcomes? Data from the CATIE Trial. Schizophr Res. 2009;107(1):22–29. doi:10.1016/j.schres.2008.09.031 PubMed
  13. Stahl SM, Cucchiaro J, Simonelli D, et al. Effectiveness of lurasidone for patients with schizophrenia following 6 weeks of acute treatment with lurasidone, olanzapine, or placebo: a 6-month, open-label, extension study. J Clin Psychiatry. 2013;74(5):507–515. doi:10.4088/JCP.12m08084 PubMed
  14. Ganguli R, Brar JS, Mahmoud R, et al. Assessment of strategies for switching patients from olanzapine to risperidone: a randomized, open-label, rater-blinded study. BMC Med. 2008;6(1):17. doi:10.1186/1741-7015-6-17 PubMed
  15. Pae CU, Serretti A, Chiesa A, et al. Immediate versus gradual suspension of previous treatments during switch to aripiprazole: results of a randomized, open label study. Eur Neuropsychopharmacol. 2009;19(8):562–570. doi:10.1016/j.euroneuro.2009.04.002 PubMed
  16. Stip E, Zhornitsky S, Potvin S, et al. Switching from conventional antipsychotics to ziprasidone: a randomized, open-label comparison of regimen strategies. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(6):997–1000. doi:10.1016/j.pnpbp.2010.05.010 PubMed
  17. Weiden PJ, Alva G, Brams M, et al. Efficacy and safety/tolerability of two approaches for switching to iloperidone in patients with schizophrenia. Poster presented at the New Clinical Drug Evaluation Unit Annual Meeting; May 29–June 1, 2012; Phoenix, AZ.
  18. McEvoy JP, Citrome L, Hernandez D, et al. Effectiveness of lurasidone in patients with schizophrenia or schizoaffective disorder switched from other antipsychotics: a randomized, 6-week, open-label study. J Clin Psychiatry. 2013;74(2):170–179. doi:10.4088/JCP.12m07992 PubMed
  19. 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
  20. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–962. doi:10.1016/S0140-6736(13)60733-3 PubMed
  21. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19(suppl 1):1–93. doi:10.2165/00023210-200519001-00001 PubMed
  22. Weiden PJ. Iloperidone for the treatment of schizophrenia: an updated clinical review. Clin Schizophr Relat Psychoses. 2012;6(1):34–44. doi:10.3371/CSRP.6.1.5 PubMed
  23. Citrome L, Cucchiaro J, Sarma K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. Int Clin Psychopharmacol. 2012;27(3):165–176. doi:10.1097/YIC.0b013e32835281ef PubMed
  24. Essock SM, Covell NH, Davis SM, et al. Effectiveness of switching antipsychotic medications. Am J Psychiatry. 2006;163(12):2090–2095. doi:10.1176/appi.ajp.163.12.2090 PubMed
  25. Weiden PJ, Preskorn SH, Fahnestock PA, et al; Roadmap Survey. Translating the psychopharmacology of antipsychotics to individualized treatment for severe mental illness: a Roadmap. J Clin Psychiatry. 2007;68(suppl 7):1–48. PubMed
  26. Citrome L, Kianifard F, Meng X, et al. Discontinuations following a switch from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia: the i-FANS study. Poster presented at American College of Neuropsychopharmacology Annual Meeting. Hollywood, FL, December 2–6, 2012.
  27. Lin CC, Chiu HJ, Chen JY, et al. Switching from clozapine to zotepine in patients with schizophrenia: a 12-week prospective, randomized, rater blind, and parallel study. J Clin Psychopharmacol. 2013;33(2):211–214. doi:10.1097/JCP.0b013e31828700c7 PubMed
  28. Tollefson GD, Dellva MA, Mattler CA, et al. The Collaborative Crossover Study Group. Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. J Clin Psychopharmacol. 1999;19(5):435–443. doi:10.1097/00004714-199910000-00007 PubMed
  29. Hermes E, Nasrallah H, Davis V, et al. The association between weight change and symptom reduction in the CATIE schizophrenia trial. Schizophr Res. 2011;128(1-3):166–170. doi:10.1016/j.schres.2011.01.022 PubMed
John W. Newcomer, MD

John W. Newcomer, MD

Executive Vice Dean, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida

Peter J. Weiden, MD

Peter J. Weiden, MD

Professor of Psychiatry, University of Illinois at Chicago

Robert W. Buchanan, MD

Robert W. Buchanan, MD

Professor of Psychiatry, University of Maryland School of Medicine Interim Director, Maryland Psychiatric Research Center, Baltimore, Maryland

Supported by an educational grant from Sunovion Pharmaceuticals, Inc.


doi:10.4088/JCP.12028br4 The Journal of Clinical Psychiatry The Primary Care Companion for CNS Disorders The CME Institute Neurology Knowledge Terms of Use Privacy Policy