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Home , Aripiprazole, Olanzapine, Ziprasidone

Switching A balanced approach

52 Current VOL. 2, NO. 8 / AUGUST 2003 p SYCHIATRY Current p SYCHIATRY to ease the transition

Elizabeth A. Winans, PharmD hen switching antipsychotics Clinical assistant professor for patients with schizophre- Departments of pharmacy practice nia, you can ease this potentially perilous passage and psychiatry W University of Illinois at Chicago by choosing the right time to switch and prevent- ing psychotic relapse. This article describes four keys to a smooth transition: • assess response and side effects with the existing medication With no standards or guidelines, • weigh the pros and cons of switching, you’re working without a net. with input from the patient or caregiver • select a replacement with characteristics Here’s evidence you need to that could improve patient function hone your clinical judgment • choose a switching strategy while consid- ering safety and efficacy data. and help patients switch safely. RISKS AND BENEFITS OF SWITCHING The two most compelling reasons to switch antipsychotics are enhanced clinical response and improved tolerability. Others may include lower medication cost, less-frequent monitoring, fewer drug interactions, or easier administration (such as once-daily versus twice-daily dosing). The greatest risk in a relatively stable patient

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Table 1 patient’s workplace or living environment Sample response criteria that may interfere with adherence to a new to evaluate an switch regimen • medication cost and coverage by third- Improved functioning party payers. • Able to be discharged from inpatient care Establishing specific response criteria for • Transition from nursing home to group home each patient (Table 1) will help you know when to • Able to hold a job or tolerate longer work continue or terminate a switch. periods • Improvement in self-care INADEQUATE RESPONSE Decreased symptoms Because antipsychotics do not eliminate all posi- • Hallucinations less frequent and bothersome tive and negative symptoms, an adequate • Delusions held less tenaciously or interfere response is considered a reasonable therapeutic less often with thinking goal. Many patients with respond • Less withdrawn or isolative • Initiates social contact adequately to traditional or atypical antipsy- 2 • Interacts appropriately with others chotics, but approximately one-third do not. Improved tolerability What is an “adequate” response? No adviso- • reduced ry groups or consensus panels have defined this • or beta-blocking agents term or set standards for when to switch. no longer needed Therefore, psychiatrists must evaluate a patient’s • subsides response to an antipsychotic by using clinical • Patient reports feeling more energetic judgment and patient/caregiver input. To gather the information you need, it is important to: • identify target symptoms at baseline • regularly monitor symptom severity, fre- is for psychotic symptoms to re-emerge. Be very quency, and intrusion on activities of careful when switching patients who: daily living and quality of life. • might harm themselves or others if their Quantitative measures. In research, response is re-emerges during the switch measured as a percent reduction in scores on • were recently stabilized after an acute standard assessments such as the Positive and psychotic episode and have been maintained Negative Syndrome Scales (PANSS). Using the for less than 6 months on the medication PANSS, however, is too time-consuming for clin- that controlled their symptoms ical practice. • cannot adhere to oral medications and are The Brief Psychiatric Rating Scale (BPRS) is being maintained on long-acting depot simpler than PANSS and can be administered formulations.1 more quickly but is less specific for negative Other factors to consider include: symptoms. Even so, using the BPRS can help • the need for more-frequent patient visits quantify baseline symptoms and monitor clinical during the transition to monitor for adverse response. It is useful to complete a BPRS rating effects prior to a switch and at subsequent visits during • the patient’s willingness to switch the transition. A >20% reduction in the total • influence of external stressors—such as score is considered an adequate response. recent bereavement—or aspects of the Qualitative measures. Rating scales do not mea- continued on page 60

54 Current VOL. 2, NO. 8 / AUGUST 2003 p SYCHIATRY Switching antipsychotics

continued from page 54

Table 2 Treatment-limiting antipsychotic side effects and options for switching

Treatment-limiting factor options

Akathisia/activation , ,

Hyperprolactinemia Any atypical antipsychotic except

Insomnia Olanzapine, quetiapine

Orthostatic hypotension

Pre-existing cardiac dysfunction , olanzapine, quetiapine, risperidone

Pre-existing Aripiprazole, quetiapine, ziprasidone

Sedation Aripiprazole, risperidone, ziprasidone

Excessive weight gain Aripiprazole, quetiapine, risperidone, ziprasidone sure patients’ and families’ subjective feelings. (EPS) and hyper- One patient may view a 50% decrease in psychot- prolactinemia may limit a patient’s tolerance of ic symptoms as extremely favorable and another an antipsychotic. Patients who are especially sen- as unacceptable. Switching therefore may be rea- sitive to EPS may not tolerate high- sonable for one patient but not for another with a agents such an similar clinical response. or even low to moderate Underdosing contributes to inade- dosages of risperidone. Others quate response, so assess whether Patients may view may not develop EPS while receiv- an antipsychotic has been given a a 50% decrease ing haloperidol or higher dosages of sufficient trial. For example, 400 in symptoms risperidone. to 800 mg/d of quetiapine is con- as very favorable Switching to an antipsychotic with sidered a therapeutic dosage, relatively less or alpha-adrener- or unacceptable assuming adequate tolerability, gic blockade may reduce problematic side but some clinicians stop increasing effects such as sedation and orthostatic the dosage below that range. Similarly, the hypotension, respectively (Table 2). usual antipsychotic trial continues at least 3 to 4 Patients vary in how well they weeks at a therapeutic dosage. tolerate other side effects, such as weight gain. For example, a 10-lb weight gain may be accept- TREATMENT-LIMITING EFFECTS able to one patient and unacceptable to another. Antipsychotic side effects that justify switching The decision to switch may be more obvious in a may be treatment-limiting or simply bothersome. patient with diabetes, for whom substantial For example, switching is necessary for antipsy- weight gain is unacceptable. chotic-induced QTc prolongation in a patient with a history of cardiac dysrhythmias and rea- SWITCHING STRATEGIES sonable for excessive daytime sedation in a No method is universally accepted for switching patient who is working or attending school. from one antipsychotic to another. In clinical

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practice and research, three common methods Figure (Figure) are used: 3 common antipsychotic • immediately discontinuing drug A while switching strategies starting drug B at full dosage • slowly tapering drug A while starting Strategy A drug B at full dosage • slowly tapering drug A while slowly increasing drug B to full dosage. Each method has advantages and disadvan- Drug A tages. Gradual cross-titration and tapering may Full dosage reduce the risk of relapse but increase the risk of Drug B side effects. Elaborate regimens may confuse some patients—especially those with cognitive Time impairment—and increase the risk for adverse Discontinue drug A immediately while simulta- events and nonadherence. neously beginning drug B at full dosage Abruptly discontinuing an agent is less con- fusing and more convenient than gradual taper- ing, but patients may experience acute withdraw- Strategy B al (as with clozapine). Finally, no guidelines exist on how quickly to make the transition when one or both medications are cross-titrated and tapered. For inpatients receiving intense monitoring, a transition may be completed in 3 to 7 days, where- Drug A Full dosage as outpatients may require 1 to 3 weeks. Drug B Recommendation. The evidence cited in the next Overlap in drug A & B section of this article suggests that any of the three methods can be used when switching Time antipsychotics, except clozapine. When switch- Slowly discontinue drug A while starting drug B at full dosage ing from clozapine, extend the cross-taper period to help minimize or eliminate rebound psychosis and symptoms. Strategy C SWITCHING FROM DEPOT TO ORAL AGENTS For patients switching from depot to oral antipsy- chotics, a 1-month cross-titration taper has been shown to be efficient and safe. Drug A Full dosage 3 Godleski et al randomized 26 patients who had Drug B received IM depot antipsychotics (haloperidol or Overlap in drug A & B decanoate) for at least 3 years to either continue the IM depot antipsychotic or switch to Time olanzapine. Although the study was designed to Slowly discontinue drug A while slowly starting assess the safety and efficacy of the switch, it also and increasing drug B to full dosage provided data on the transition method. continued

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Subjects switching to olanzapine received Olanzapine. When switching to olanzapine, a their routine depot plus olanzapine, 10 direct switch or cross-titration tapering appear to mg/d for 1 month, followed by olanzapine be viable options. monotherapy (5 to 20 mg/d) for 2 months. Those In one multicenter, open-label study,2 108 who continued IM depot therapy were main- patients were randomly assigned to olanzapine, tained at a stable dose and dosing interval for 3 10 mg/d, after abruptly discontinuing a previous months. Safety and efficacy data were collected at antipsychotic (direct switch) or by cross-titration baseline and monthly. tapering in a 1:1 fashion. Patients in the cross- Patients receiving olanzapine improved on titration group started olanzapine and discontin- several efficacy measures, although the clinical ued their original antipsychotics across 2 weeks. relevance was minimal. For example, their mean Olanzapine dosages were adjusted as needed PANSS total score decreased 3.23 points. One from 5 to 20 mg/d. patient—in the control group—was hospitalized. At study entry, approximately 95% of subjects Those who received olanzapine preferred this in the direct-switch group and 85% in the cross- agent to the IM depot formulations and chose to titration taper group were taking at least one typ- continue daily olanzapine therapy. Adverse events ical antipsychotic—usu- did not increase significantly while ally haloperidol. A switch was patients received IM depot injec- considered successful if a patient tions plus olanzapine. Taper clozapine completed the 6-week trial without across at least 1 to 2 psychotic symptom worsening or SWITCHING ORAL AGENTS weeks to minimize EPS. Clozapine. When risperidone potential for The 92 (85%) subjects who complet- entered the U.S. market in the psychotic rebound ed the study comprised similar percent- 1990s, a number of patients who ages from both groups. Their scores on had been treated with clozapine the PANSS total and subscales and were abruptly switched to risperidone. Many Clinical Global Impression (CGI) experienced acute symptom exacerbation,4,5 scale also were similar. including some whose rebound psychosis was The most common adverse events were som- more severe than their original symptoms. Other nolence, , and headache in the direct- adverse effects—including nausea, diarrhea, switch group (all 11%), and (15%), vomiting, headache, restlessness, and sweating— headache (9%), insomnia (7%), and increased have been attributed to cholinergic rebound appetite (7%) in the cross-titration group. caused by abruptly discontinuing clozapine. Differences in these percentages were not statisti- To minimize the potential for rebound psy- cally significant. chosis and cholinergic symptoms, taper clozap- EPS and improved significantly in ine across a minimum of 1 to 2 weeks. When both groups (p< 0.01) after switching to olanza- you need to discontinue clozapine immediate- pine. Thirteen (24%) patients in the direct-switch ly—such as for patients experiencing serious group and 17 (32%) in the cross-titration taper hematologic effects—adding an anticholinergic group required at least one dose of benztropine. such as benztropine may minimize the cholin- Use of concomitant medications was similar. ergic rebound. Quetiapine can be abruptly discontinued with Risperidone. No studies have formally assessed minimal risk of adverse events when initiating methods for switching patients to risperidone. another antipsychotic.

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Cutler et al6 switched 50 stable patients who All patients’ total score and positive and neg- had been treated with risperidone, , ative PANSS subscale scores improved signifi- haloperidol, or haloperidol plus benztropine. cantly (p<0.01) across 6 weeks, although these The original antipsychotics were abruptly discon- data represent symptom changes after switching tinued, and quetiapine was initiated in a dose- to ziprasidone. No efficacy escalating fashion and then or safety data were reported maintained at 300 mg/d for 12 during switching. The authors con- days. After that, quetiapine was All three strategies cluded that patients could switch suc- abruptly discontinued and were well-tolerated cessfully to ziprasidone over a relatively patients were assessed for side when switching short period using a variety of methods. effects, including EPS. to ziprasidone or In another study, Stip8 switched 54 Most patients’ BPRS or CGI- aripiprazole patients to ziprasidone from haloperidol. Severity of Illness scores did not All received ziprasidone, 40 mg bid for 2 change significantly. Two patients days and then 80 mg bid. Haloperidol (4%) experienced psychotic relapse during the was discontinued: switch. The authors speculated that these relapses • immediately on day 1 might have been related to subtherapeutic queti- • after the dosage was decreased by 50% for 7 apine dosing. Transient nausea and vomiting were days reported after quetiapine was discontinued. • or after continuing the full dosage for 2 Ziprasidone. When switching from another antipsy- days, then taking 50% of the initial dosage chotic to ziprasidone, all three strategies appear well for 5 days. tolerated and maintain symptom control. All patients maintained symptom control while Using randomized, open-label trials, Weiden switching, and 40 of 54 completed the trial. et al7 investigated strategies for switching patients Among responders, BPRS and CGI scores to ziprasidone from olanzapine, risperidone, and improved significantly across 6 weeks, and EPS traditional antipsychotics. All participants were improved as expected. diagnosed with schizophrenia or schizoaffective Aripiprazole. Direct-switch and cross-titration disorder and had experienced partial or inade- tapering methods appear to be effective and well- quate response or side effects with their original tolerated when switching stable patients to ari- antipsychotics. piprazole. Patients were assigned to one of three switch- In an 8-week, randomized, open-label trial, ing strategies: Casey et al9 switched 311 outpatients with schiz- • abruptly discontinue the initial antipsy- ophrenia or to aripipra- chotic zole. The patients—who had been taking stable • decrease the initial antipsychotic’s dosage dosages of haloperidol, , risperi- by 50% for 1 week, then discontinue it done, or olanzapine for at least 1 month—were • gradually taper the initial antipsychotic, randomly assigned to three groups: so that subjects received 100% for 3 days of • group 1 immediately discontinued the pre- ziprasidone treatment, 50% for the next 4 vious antipsychotic and started aripiprazole, days, and none thereafter. 30 mg/d For all three strategies, ziprasidone was start- • group 2 started aripiprazole, 30 mg/d, and ed at 80 mg/d for 2 days, with dosing adjusted as discontinued the previous antipsychotic needed to 40 to 160 mg/d. across 2 weeks continued

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• group 3 started aripiprazole (10 mg/d in week 1, 20 mg/d in week 2, and 30 mg/d in Related resources week 3) and tapered the previous antipsy- Borison RL. Changing antipsychotic medication: guidelines on the transition to treatment with risperidone. The Consensus Study chotic (50% less in week 1, another 50% less Group on Risperidone Dosing. Clin Ther 1996;18(4):592-607. in week 2, then discontinued). Investigators assessed treatment efficacy DRUG BRAND NAMES Aripiprazole • Abilify Haloperidol • Haldol using the PANSS and CGI at baseline and weeks Benztropine • Cogentin Olanzapine • Zyprexa 4 and 8. They questioned patients about adverse Chlorpromazine • Thorazine Quetiapine • Seroquel Clozapine • Clozaril Risperidone • Risperdal events at each follow-up visit. Fluphenazine • Prolixin Ziprasidone • Geodon Nearly three-fourths (72%) of patients com- pleted the trial. Discontinuation rates were 31% DISCLOSURE in group 1, 34% in group 2, and 19% in group 3. Dr. Winans is a consultant for Bristol-Myers Squibb Co. and is a speaker for Inc., Abbott Laboratories, and Bristol-Myers Squibb Co. Efficacy, safety, tolerability, and incidence of dis- continuation because of worsening psychosis were comparable across groups. Similar percentages of patients in each group Hospitalization rates were comparable among reported one or more adverse event (89%, 89%, the three groups. and 81% for groups 1, 2, and 3, respectively). All groups improved slightly on the Barnes Most adverse events were described as mild to Akathisia Scale, Simpson Angus Rating Scale, and moderate. Insomnia was reported most frequent- Abnormal Involuntary Movement Scale. Few ly. Other adverse effects that occurred in >10% of patients in each group required benztropine (2%, subjects included nausea, akathisia, anxiety, psy- 4%, and 7% for groups 1, 2 and 3, respectively). chosis, headache (groups 2 and 3), somnolence, lightheadedness (groups 1 and 2) vomiting References 1. Weiden PJ, Aquila R, Dalheim L, Standard JM. Switching antipsy- (group 2 only), agitation (group 3 only), and diar- chotic medications. J Clin Psychiatry 1997;58(suppl 10):63-72. rhea (group 2 only). 2. Lee CT, Conde BJL, Mazlan M, et al. Switching to olanzapine from previous antipsychotics: a regional collaborative multicenter Seven patients were hospitalized for serious trial assessing 2 switching techniques in Asia Pacific. J Clin adverse events—usually worsening psychosis. Psychiatry 2002;63:569-76. 3. Godleski LS, Goldsmith J, Vieweg V, et al. Switching from depot antipsychotics to olanzapine in patients with chronic schizophrenia. J Clin Psychiatry 2003;64:119-22. 4. Clinical implications of clozapine discontinuation. Reports of an NIMH workshop. Schizophr Bull 1995;21(2): 333-7. Inadequate response and treatment- 5. Shiovitz TM, Welke TL, Tigel PD, et al. Cholinergic rebound and rapid psychosis following abrupt clozapine withdrawal. Schizophr limiting side effects are the two most Bull 1996;22(4):591-5. common reasons for switching 6. Cutler AJ, Goldstein JM, Tumas JA. Dosing and switching strate- antipsychotics. Successful switching gies for quetiapine fumarate. Clin Ther 2002; 24(2):209-22. 7. Weiden PJ, Simpson G, Potkin S. Therapeutic response in stable requires balancing risks and benefits outpatients switched to ziprasidone (poster). Stockholm, Sweden: Association of European Psychiatrists 11th Congress, May 4-8, while working with the patient or 2002. caregiver. For safety, set goals and 8. Stip E. Haloperidol to ziprasidone switching strategies in schizo- monitor for adherence and relapse. phrenia (abstract). Eur Neuropsychopharmacol 2001;11(suppl 3):s272. 9. Casey DE, Carson WH, Saha AR, et al. Switching patients to arip- iprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology 2003;166(4):391-9. Bottom Line

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