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CATIE can be viewed as a switch study. Switches offer both opportunity and risk. Data from CATIE demonstrate differences in overall effectiveness, but these differences depend on the individual patient context.
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After reading this article, you will be familiar with:
• The different arms of the CATIE study
• The use of number needed to treat and number needed to harm in appraising the clinical relevance of study results
• CATIE efficacy, tolerability, and safety results for the atypical antipsychotics as well as the representative typical antipsychotic, perphenazine
• The advantages/disadvantages of one antipsychotic over another
Who will benefit from reading this article?
Psychiatrists, child and adolescent psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing and certification boards.
Efficacy variations among the atypical and typical antipsychotics result in overlaps between the 2 groups.1 Adverse-effect profiles differ as well. In general, typical antipsychotics have a greater propensity to cause extrapyramidal side effects, tardive dyskinesia, and prolactin elevations than do atypical anti-psychotics. The adverse effects associated with some atypical antipsychotics are more weight gain and greater disturbances in lipid and glucose regulation than are associated with typical antipsychotics. However, there is considerable heterogeneity among the individual agents in both classes and overlapping adverse effects.
According to Sackett and colleagues,2 the philosophy of evidence-based medicine requires the thoughtful clinician to incorporate the best available research findings into an individualized treatment plan, and to take into account clinical experience and patient preferences. When selecting antipsychotics for patients with schizophrenia, the prescribing physician can approach this decision-making process using these principles of evidence-based medicine.
On the basis of the results from the NIMH-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), this article reviews the principles of antipsychotic therapy selection based on individual patient profiles as it pertains to perphenazine (the representative typical anti-psychotic in the CATIE study), olanzapine, risperidone, quetiapine, ziprasidone, and clozapine. Using a basic tool of evidence-based medicine-effect size as measured by number needed to treat-demonstrates that we are better off having choices.
Simone is a 45-year-old African American woman whose schizophrenia was diagnosed when she was 22 years old. She has had about 5 brief hospitalizations for exacerbations of her symptoms, usually precipitated by nonadherence when her medications were changed to something she did not agree with. She lives in a basement apartment owned by her family and attends a day treatment program 3 times a week. Simone smokes about 10 cigarettes a day when she is able to afford them. She does not use street drugs or alcohol. Simone has a fraternal twin, Sabella, who also has schizophrenia.
Simone responds reasonably well to quetiapine or risperidone, but not to haloperidol, and she objects to extrapyramidal side effects, particularly akathisia. Simone’s mother and all of her maternal aunts have type 2 diabetes mellitus. Her body mass index is 29 kg/m2, and she eats high-fat foods and does not exercise. She is willing to take either quetiapine or risperidone and her clinician prescribes generic risperidone.
Simone presents with a number of conflicting issues, and the best medication option for Simone at this juncture is difficult to immediately ascertain. Fortunately, there are clinical trials that can help inform the clinician in making thoughtful individualized treatment decisions about antipsychotic medication switches. Simone is representative of ambulatory patients with schizophrenia who have been ill for a decade or more. Thus, she resembles the patients enrolled in the CATIE schizophrenia studies.3-6
Approximately 1500 patients participated in at least one part of CATIE, and the study remains the largest randomized pragmatic clinical trial to date that compares the overall relative effectiveness of several of the atypical antipsychotics with each other as well as with a representative typical antipsychotic (perphenazine). Time to all-cause discontinuation was the primary outcome measure and represents the “real-world” usefulness of a medication. The assumption is that a patient will continue to use a medication (and a clinician will continue to prescribe it) if the medication is considered by all parties to be effective, safe, and tolerable.
Number needed to treat
One of the basic tools of evidence-based medicine used to appraise clinical trial data is number needed to treat.7 Number needed to treat answers the question: for how many patients do I need to prescribe medication X instead of medication Y before I would expect to encounter one additional success? If the number needed to treat for success of medication X versus medication Y is 5, then it would take 5 patients to be treated with X instead of Y before one additional patient has a successful outcome. The higher the number needed to treat, the less of a difference there is between medications X and Y. The lower the number needed to treat, the more compelling the difference is. (See Sidebar for how to calculate number needed to treat.)
CATIE outcomes can be reinterpreted using number needed to treat.8 Depending on the phase of CATIE, different antipsychotics had different rankings for overall effectiveness.9 The usefulness of CATIE in informing medical decision making is that the study consisted of several phases during which patients could discontinue their initial randomized medication and be re-randomized to another. Thus CATIE actually mimics clinical practice: if one antipsychotic does not work for any reason, another antipsychotic is tried. (See Table 1 for a summary of CATIE methodology and Table 2 for a summary of patient characteristics.)
CATIE phase 1
Phase 1 demonstrated that all-cause discontinuation was lowest with olanzapine; risperidone and perphenazine also had advantages in terms of number needed to treat. Switching away from risperidone or olanzapine may also have an impact on all-cause discontinuation. This was observed in a post hoc analysis of patients randomly assigned to olanzapine or risperidone who also continued to take their baseline medication. These patients had significantly longer times until discontinuation than those who switched antipsychotics.10 Thus, switching antipsychotics is not necessarily a benign process.
An important caveat is that we do not know what exactly motivated the patients to participate in CATIE, nor do we know with any precision how effective or tolerable their medication regimens were before randomization.
What are the relative rankings of the different antipsychotics in phase 1? We can calculate the number needed to treat for pair-wise comparisons on all-cause discontinuation. The 95% confidence interval (CI) is provided for all comparisons that were statistically significant at the P < .05 level (Table 3).
The lower the number needed to treat value, the bigger the advantage is for the antipsychotic relative to its comparator. For example, for every 6 patients randomized to olanzapine instead of quetiapine in phase 1, one additional patient will have completed the entire 18 months on the initially randomized medication (ie, successful in avoiding all-cause discontinuation). Likewise, for every 13 patients randomized to risperidone instead of quetiapine in phase 1, one additional patient will have avoided all-cause discontinuation. For this latter comparison, the 95% CI is considered “wide,” with 95% certainty, the actual difference between risperidone and quetiapine on all-cause discontinuation is somewhere between a low of every 7 patients to a high of every 54 patients.
CATIE interim phase 1B
CATIE also answers the question about what agent to switch to after a patient has had an unsuccessful trial with perphenazine. Phase 1B was an interim phase for those patients who had been randomized to perphenazine in phase 1 but who discontinued for any reason. Inadequate therapeutic effect was the reason why 48% of the participants in phase 1B discontinued perphenazine, and 32% discontinued it because of unacceptable adverse effects. Thus, the enrollees in phase 1B represent patients who did not do well enough because of either efficacy or tolerability issues on an older agent with relatively “tight” dopamine D2 receptor binding (perphenazine). In this phase, quetiapine (and olanzapine) performed relatively well, whereas risperidone, a “tighter” D2 blocking agent than olanzapine or quetiapine, did not (Table 4). This difference between risperidone and quetiapine is the opposite of what was observed in phase 1 and, as will be discussed later, in phase 2T. Phase 1B demonstrates that number needed to treat values for all-cause discontinuation are highly dependent on which phase of CATIE is being scrutinized.
CASE VIGNETTE cont’d
In view of the relative rankings of the different antipsychotics in CATIE phase 1, generic risperidone was not an unreasonable choice, especially given Simone’s past history of response. Moreover, should adherence become an issue, the availability of a depot formulation of risperidone is a definite plus. Unfortunately, 2 months after being placed on treatment with 4 mg of risperidone per day, Simone complained of feeling restless. Her clinician was of the opinion that the patient’s restlessness was due to akathisia. Simone was no longer willing to take risperidone. She did not want to wait to see if a reduction in dosage would decrease her subjective restlessness, nor did she want to take pro-pranolol to see if that would relieve her symptoms. Given Simone’s strong family history for type 2 diabetes mellitus and Simone’s elevated weight, as well as her unhealthy lifestyle, her clinician decided to treat her with ziprasidone. CATIE supports this decision as well.
CATIE phase 2T: tolerability
The so-called ziprasidone pathway for phase 2, known as phase 2T, was designed to test whether ziprasidone had advantages over the other atypical antipsychotics for patients who discontinued phase 1 early because of poor tolerability. In reality, phase 2T is challenging to interpret because approximately equal numbers of patients who discontinued phase 1 because of poor efficacy entered phase 2T as those who discontinued phase 1 because of poor tolerability. The number needed to treat and the 95% CI for all-cause discontinuation are summarized in Table 5.
For all-cause discontinuation in phase 2T, the only 2 statistically significant results for number needed to treat were the comparisons of olanzapine or risperidone versus quetiapine. For every 6 patients randomized to olanzapine, or every 5 patients randomized to risperidone, instead of quetiapine, there was 1 additional patient taking olanzapine or risperidone who did not discontinue therapy prematurely. Ziprasidone did not demonstrate superiority on the global outcome of all-cause discontinuation. However, phase 2T did confirm the benign metabolic profile for ziprasidone and there were fewer discontinuations because of weight or metabolic concerns (Table 6).
Of particular interest are the patients who gained more than 7% of their initial body weight. Of the 61 patients who did so in CATIE phase 1, 42% of those randomized to ziprasidone in phase 2T lost over 7% of their body weight, compared with 20% for risperidone, 7% for quetiapine, and 0% for olanzapine. This translates to number needed to treat comparing ziprasidone with risperidone (5), quetiapine (3), and olanzapine (3). For every 3 patients who gained more than 7% of their baseline weight in phase 1 and who were subsequently randomized to ziprasidone in phase 2 instead of olanzapine or quetiapine, an additional case of weight loss greater than 7% was observed.
CASE VIGNETTE cont’d
Simone was given ziprasidone with some concerns on her part because she had never taken it before and was unsure whether it would work for her. She was also concerned about the need to change her schedule to take ziprasidone with a meal.11 However, she was interested to see if her weight would be better controlled.
Ongoing monitoring of weight continues to be necessary and amenability to a weight reduction program needs to be assessed. Monitoring weight at each patient visit allows the clinician to catch a problem early, before substantial weight gain has set in. It also underscores to both the patient and the clinician the importance of physical fitness. Weight management strategies include both psychoeducational and medication interventions; the latter technique is less successful than the former.12
CASE VIGNETTE cont’d
Simone is not particularly worried about rehospitalization-her symptoms were successfully managed throughout the crisis by increasing her attendance at her day treatment program from 3 times a week to every day. Her sister, Sabella, however, has had a stormier course, with rehospitalizations occurring almost every 6 months. Both Simone and Sabella are worried about their weight. Can we quantify trade-offs between avoidance of hospitalization versus weight gain?
The CATIE study informs us about balancing the risk of weight gain versus the risk of hospitalization caused by exacerbation of schizophrenia. In phase 1, the numbers needed to treat to avoid hospitalization for exacerbation of schizophrenia based on 1-year risk ratios (hospitalizations per total person-years of exposure) are listed in Table 7.13
Although olanzapine had advantages regarding avoidance of hospitalization, it was associated with higher rates of weight gain in excess of 7% of baseline. Pairwise comparisons can be made and number needed to harm for weight gain can be calculated. Number needed to harm is an analogue of number needed to treat and is used when referring to undesirable outcomes. It is calculated the same way as number needed to treat. Table 8 provides the number needed to harm for weight gain.
For every pair-wise comparison, with the exception of olanzapine versus risperidone, avoidance of a hospitalization event would be encountered more frequently than weight gain in excess of 7% of baseline (number needed to treat is lower, ie, stronger, than number needed to harm). Ratios of number needed to harm to number needed to treat have been used to describe the likelihood of being helped or harmed.14 However, some patients may gain substantially more than 7% of their baseline weight. Weight gain and robust efficacy in the same patient poses a clinical dilemma.
Moreover, even though number needed to treat and number needed to harm can help predict how often events can occur, there are no guarantees of weight gain or loss, or of a drug’s effectiveness. The patient’s history remains the best predictor of treatment success or failure.
CASE VIGNETTE cont’d
After unsuccessful trials of several antipsychotics, both Simone and Sabella are fed up. They want to try clozapine. What does CATIE tell us about switching from a first-line atypical antipsychotic to clozapine?
CATIE phase 2E: efficacy
The “clozapine pathway” of phase 2 of CATIE, known as phase 2E, was designed to test what advantages there might be for switching to clozapine for patients who discontinued their phase 1 or phase 1B atypical antipsychotic because of poor efficacy. Fewer patients randomized to olanzapine in phase 1 entered phase 2E than 2T (19% vs 26%), but more patients who were randomized to quetiapine in phase 1 entered phase 2E than 2T (37% vs 31%). A possible confounder is that patients who entered phase 2E knew they could be randomized to clozapine, and once randomized knew if they were actually getting open-label clozapine versus double-blinded olanzapine, quetiapine, or risperidone. Hence, if they really wanted clozapine and did not get randomized to it, they may have been inclined to discontinue their anti-psychotic. The number needed to treat and the 95% CI for all-cause discontinuation are summarized in Table 9.
Statistically significant differences are evident for the comparisons of clozapine with risperidone or quetiapine; the number needed to treat showed an advantage for clozapine every 4 or 3 patients, respectively, in terms of all-cause discontinuation. The number needed to treat for clozapine versus olanzapine was 7, which indicates a respectable effect size difference that could have been statistically significant if only the sample size had been larger.
CASE VIGNETTE cont’d
Simone and Sabella have heard that clozapine may be associated with hypersalivation. They ask how frequent a problem this is.
The importance of context when looking at treatment advantage
Sialorrhea is a common side effect of clozapine. Inspection of the clozapine product label reveals a reported frequency of 31% for hypersalivation.15 CATIE provides enough information to calculate the number needed to harm for sialorrhea, comparing clozapine with quetiapine, olanzapine, and risperidone, as outlined in Table 10.
For every 3 patients randomized to clozapine versus quetiapine, one additional case of sialorrhea was encountered. This is a strong effect size and emphasizes how common this adverse effect is with clozapine. However, if good efficacy is achieved, patients who take clozapine will tol-erate hypersalivation and will not stop their medication.
Individual patients have their own preferences and values regarding efficacy and tolerability goals. These may differ from what the clinician has in mind. Thus, although the practitioner may want to prioritize the diminution of hallucinations and delusions, the patient may desire mainly to feel less anxious and less dysphoric. Similarly, different patients may find different adverse effects of medications distressing-some may abhor tremors but others may not mind them.
Pragmatic clinical trials (such as CATIE) provide generalizable data that can be incorporated into medical decision making. In the different phases of CATIE, advantages were evident for each of the atypical antipsychotics and for the representative typical antipsychotic perphenazine, but all in different contexts.
Olanzapine had advantages in terms of all-cause discontinuation and efficacy, particularly in phase 1. It appears that the efficacy advantage of olanzapine drove its overall lower all-cause discontinuation rate. The disadvantage of olanzapine was discontinuation because of weight gain or metabolic effects; although this disadvantage was statistically significant, it did not reach the same level of magnitude as the number needed to treat advantage for efficacy.8
Risperidone and perphenazine had advantages over quetiapine in phase 1 in terms of number needed to treat for all-cause discontinuation. Quetiapine (and olanzapine) had advantages in terms of all-cause discontinuation in phase 1B where perphenazine had failed. Clozapine was superior to risperidone and quetiapine for patients who discontinued an antipsychotic in phase 1 (or 1B) because of poor efficacy. Risperidone had advantages in terms of overall tolerability in phases 1, 2E, and 2T. Ziprasidone had the most benign metabolic profile, and in phase 2T it was associated with a higher likelihood of weight loss for patients who gained more than 7% of their initial body weight in phase 1.
CATIE can be viewed as a switch study. Switches offer both opportunity and risk. Data from CATIE demonstrate differences in overall effectiveness, but these differences depend on the individual patient context. Questions to ask include:
• Did therapy with a “tight” D2 binding agent fail?
• Did therapy fail because of lack of efficacy or tolerability?
• Is weight gain greater than 7% the predominant concern?
• Is the risk of hospitalization the predominant concern?
It will be necessary to match the expectations and requirements of the individual patient to a specific medication-one size does NOT fit all. Treating clinicians need access to all these medications to optimize treatment for each patient.
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10. Essock SM, Covell NH, Davis SM, et al. Effectiveness of switching antipsychotic medications. Am J Psychiatry. 2006;163:2090-2095.
11. Citrome L. Using oral ziprasidone effectively: the food effect and dose-response. Adv Ther. 2009;26:739-748.
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15. Novartis. Clozaril (clozapine) tablets. Prescribing information. Revised July 2009. http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf. Accessed November 17, 2009.
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17. Miller DD, McEvoy JP, Davis SM, et al. Clinical correlates of tardive dyskinesia in schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res. 2005;80:33-43.