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Clinical and Research News
Drug Continuity May Aid In Better Treatment Outcomes
Psychiatric News
Volume 41 Number 24 page 18-30

A fresh look at the data from phase 1 of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study, funded by the National Institute of Mental Health (NIMH), indicates that patients who stayed on their initially assigned antipsychotic medication the longest may have done so, in part, because it was the same drug they were taking prior to entering the study. In other words, continuity appears to have helped foster longevity.

The new analysis, by Susan Essock, Ph.D., a professor and director of the Division of Health Services Research in the Department of Psychiatry at Mt. Sinai School of Medicine, appears in the December American Journal of Psychiatry.

Essock was not originally part of the CATIE research team, but she approached principal investigator Jeffrey Lieberman, M.D., director of the New York State Psychiatric Institute, with the idea of analyzing the effects of switching versus not switching medications at initial drug assignment. In keeping with NIMH's vision of open access, the CATIE data were made available to Essock.

Essock's main question was deceptively simple: is it more advantageous to continue taking the medication being received at entry into a clinical trial or to switch to a different medication at the start of the study? If staying with the same medication was more advantageous than switching, Essock expected that those who stayed with the same medication would have longer times to discontinuation for any reason, the primary outcome measure in the CATIE trial.

Each of the patients entering the trial, along with their clinicians, presumably were at least somewhat dissatisfied with the antipsychotic being taken; otherwise, entering a clinical trial would not likely have been a consideration.

In CATIE phase 1, 23 percent of participants randomly assigned to olanzapine (Zyprexa) were already taking olanzapine, 18 percent of those randomly assigned to take risperidone (Risperdal) were already taking risperidone, and 5 percent assigned to quetiapine (Seroquel) were already taking quetiapine prior to the study. Less than 5 percent of patients randomly assigned by the study to take perphenazine or ziprasidone were taking those drugs prior to entering the study. Because of the low number of patients involved, statistical comparisons involving quetiapine, perphenazine, and ziprasidone were not done, due to an inherent lack of statistical significance.

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To investigate the "staying versus switching" question completely, though, Essock and her collaborators had to approach the question from both sides of the study's baseline: the first subanalysis involved the group of patients randomly assigned to either olanzapine or risperidone upon entering the study and investigated how well they had done based on whether they stayed with their pre-study medication or switched to another study drug. The second subanalysis involved the group of patients who were taking either olanzapine or risperidone prior to entering the study and investigated how well they fared if they stayed versus switched.

The researchers had already hypothesized that "stayers" would have better outcomes; that is, continuity of medications would lead to longer times to drug discontinuation. But if the "stayers" did fare better, Essock and her colleagues reasoned, the collective" better" results seen with those patients could potentially significantly bias the overall phase 1 results. Therefore, they also wanted to determine whether the phase 1 results would be different if study participants randomly assigned to stay with their medication were excluded from the CATIE phase 1 analysis (therefore removing the potential bias).

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Essock and her colleagues found that patients who were randomly assigned to either olanzapine or risperidone and were "stayers" did indeed have the lowest rates of discontinuation of their study medications overall, compared with "switchers" who took olanzapine or risperidone during the study after switching from a different baseline medication. In addition, the researchers found that patients staying with olanzapine were significantly less likely to stop taking their study drug, compared with those staying on risperidone.

Essock and her colleagues wrote, "Although both staying with one's baseline medication and being randomly assigned to double-blind olanzapine treatment led to longer times to discontinuation, there was no extra synergistic effect of staying with olanzapine."

Second, patients who were taking olanzapine prior to entering the study and were randomly assigned to stay on olanzapine during the study fared significantly better, with longer average times to discontinuation, compared with patients assigned to switch drugs at study entry. In contrast, for those who were taking risperidone prior to entering the study, there was no significant difference between them and those who switched to any of the other four drugs.

Finally, Essock looked at the outcome measures for time to discontinuation for any cause from CATIE phase 1 treatment, with all patients who were" stayers" excluded from the analysis. With stayers removed, the magnitude of the differences between olanzapine and the other drugs was smaller; however, the general pattern was the same for discontinuation of phase 1 treatment for any reason.

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In everyday clinical practice, patients with schizophrenia often change medications in an attempt to find a drug that offers better control of symptoms, fewer adverse effects, or both.

Yet, "the switch or stay question is harder to answer in psychiatry than in most other medical specialties," pointed out John Davis, M.D., a professor of psychiatry at the University of Illinois at Chicago; Stephen Marder, M.D., a professor of psychiatry at the University of California at Los Angeles; and Carol Tamminga, M.D., a professor of psychiatry at the University of Texas Southwestern Medical School, in an editorial accompanying the report.

"Schizophrenia almost always responds incompletely to treatment," they continued, and "a patient's optimal response is always a matter of judgment and usually difficult to assess, quantitate, and record in the chart." It is also important "that clinicians monitor and record efficacy and side-effect changes, thereby providing a picture over time of how well a patient is doing... .Careful monitoring may preserve the clinically useful information of why a patient may do better with a given drug."

The findings of the current report, Essock and her colleagues said, indicate that the potential success of a switch in medications is "a function both of the medication being switched from and the medication being switched to, and that switches have only modest success rates," at least among the medications used during CATIE phase 1 in the patient population enrolled in CATIE.

"On average, it may be better to stay with olanzapine," Essock and her colleagues said, "than to switch to one of the other antipsychotics used in phase 1." However, those who switched to olanzapine for phase 1 were more likely to discontinue it due to intolerability compared with those who stayed with olanzapine at study entry. Those who switched to olanzapine were also more likely to discontinue it due to intolerability compared with both patients who stayed on risperidone or switched to risperidone. As a result, Essock and her colleagues noted," these limitations in olanzapine's tolerability acted to offset some of its superior efficacy as originally reported."

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"These findings suggest that unless the clinical situation requires a medication change, prescribers should take steps to optimize current medication regimens (e.g., via dosage changes, behavioral or psychosocial interventions, adjunctive medications) before switching medications," the researchers wrote.

Yet, in the accompanying editorial, the authors pointed out that the decision to stay or switch isn't all that straightforward.

"If staying with olanzapine treatment," they wrote, "is associated with fewer discontinuations for psychosis, but changing to another antipsychotic is associated with a lower risk of serious side effects such as heart disease, then what should the clinician do?"

Patients and clinicians, they confirmed, "face this very difficult question nearly every day."

What Essock and her colleagues stress is "working diligently with patients to maximize the effectiveness of the current antipsychotic, before taking on the risks associated with a medication change, in hopes that the next one will be more satisfactory."

"Effectiveness of Switching Medications" and the editorial "Switch or Stay?" can be accessed at<www.ajp.psychiatryonline.org> under the December issue.

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