Our results suggested a high discontinuation rate following a relatively short duration of drug treatment (median of 26 weeks), lack of significant improvement in psychopathology (on BPRS), high incidence of metabolic syndrome (36.5% in one year), and of serious (23.7%) and non-serious (50.8%) adverse events with AAPs. These results are worrisome since we had given a choice to the patients and their psychiatrists to exclude one or two of the four AAPs for possible safety or effectiveness concerns. The clinicians could choose the daily dosage and change it as needed at any time. The daily dosages of the AAPs prescribed were relatively low. Thus, we had sought to give all the study AAPs the best chance of proving safe and effective, as is done in good clinical practice.
Designing a pragmatic clinical trial involves trade-offs between an ideal experimental design and practical considerations that would enhance its applicability to routine clinical management of patients. There is a certain amount of bias in almost every clinical trial. We believe that the Equipoise-Stratified Randomization provided the least amount of bias for this “real world” type of investigation. Only 16.6% of the patients agreed to be randomized to all four medications. Thus, a traditional randomization design would have resulted in exclusion of 83.4% of the patients who participated in this study and thus, the study sample would not have been representative of the population to which clinical decisions are relevant. The conclusions of a traditional randomized trial apply only to those patients who are willing to accept randomization to any one of the drugs in that trial. Therefore, the success or failure rate of a drug when compared to placebo may not be the same as that when compared to an active comparator, not only because the comparator is different, but also because the population sampled is different – e.g., patients who refuse a placebo trial are different from those who refuse a trial in which olanzapine is used.
The flexibility that we offered to the patients and their treating psychiatrists in allowing them to exclude one or two AAPs because of past experience or anticipated side effects led to expected differences in baseline characteristics of the medication groups. Thus, the patients who seemed to have a greater risk of developing Metabolic Syndrome (e.g., high BMI) excluded olanzapine as a possible medication due to a fear of additional metabolic problems19;37
. Similarly, there is a channeling or allocation bias38
, when claimed advantages of a new drug channel it to patients with special pre-existing morbidity - e.g., the reportedly lower propensity of aripiprazole to cause adverse metabolic effects might have resulted in a greater likelihood of its being included in the list of medications acceptable for patients at risk of Metabolic Syndrome, such as those with abdominal obesity or elevated fasting blood glucose levels. Therefore, our findings of baseline differences among patient groups in different strata support the pragmatic value of the present study – in real life, clinicians prefer aripiprazole to olanzapine for patients at higher risk of Metabolic Syndrome. Yet, the reported metabolic advantages of aripiprazole compared to olanzapine were not borne out in this study. The higher incidence of Metabolic Syndrome with aripiprazole likely was related to the fact that the patients who included that drug in their list of acceptable medications were at a greater risk of developing the Metabolic Syndrome at baseline than those who opted for olanzapine. The main point here is that aripiprazole did not prove to be safe in high-risk patients.
Metabolic Syndrome is reported to be associated with increased risk of diabetes, obesity, hypertension, and heart disease39;40
. The prevalence of Metabolic Syndrome in the older adults of the general population is reported to be 24%–44%41–44
. The high baseline prevalence as well as elevated one-year incidence rates of Metabolic Syndrome observed in our patients raise concerns about psychiatric patients’ cardiometabolic and cerebrovascular health.
Quetiapine was removed from the trial before the study was completed because of the observed high incidence of SAEs36
. This finding is consistent with a report by Tiihonen et al45
, who found that the standardized mortality rate with quetiapine in patients with schizophrenia was twice that with clozapine. Similarly, quetiapine was recently removed by the U.S. Central Command from its approved formulary list due to medication- associated mortality46
Our study has several limitations. This was a sample of patients aged >40; hence, our results may not generalize to younger patients. Some patients had been treated previously with different antipsychotics for varying duration, and those drugs might have contributed to metabolic changes seen early in our trial. Our sample included patients with different psychiatric disorders. The sample sizes in individual diagnostic groups were inadequate for testing small to medium size differences. Our study findings may not be applicable to newer antipsychotics such as lurasidone or iloperidone. Although we sought to make our study design mimic clinical practice, the two are not the same, and therefore, our results may not apply fully to everyday care. For example, in the real world, patients are not randomized. Lastly, it is usually not possible to conclude that an SAE observed during the treatment is causally related to that drug.
Notwithstanding the limitations, the results of our study are sobering. One-half of the patients remained on the assigned drug for less than six months. Furthermore, there was no significant improvement in BPRS total or psychosis subscale scores over a six-month period, and there was a high incidence of Metabolic Syndrome, SAEs, and NSAEs. While there were a few significant differences among the four AAPs included in this study, the overall risk-benefit ratio for the AAPs in patients over age 40 was not favorable, irrespective of diagnosis and drug.
The use of AAPs in older psychotic patients presents a major clinical dilemma. Psychotic disorders, including those associated with conditions other than schizophrenia, have severe adverse consequences for the medical health, career, family, and quality of life of sufferers. AAPs, although not approved for these conditions, are commonly used off-label in these patients, and there are few, if any, evidence-based treatment alternatives in older patients with psychotic disorders. Indeed, Tiihonen et al45
reported that no treatment with an antipsychotic was associated with higher mortality than treatment with an AAP. Thus there are risks associated with either no treatment or treatment with other medications including typical antipsychotics and mood stabilizers35
. At the same time, the low safety and effectiveness of AAPs found in our study, along with the high costs of these medications, make their use problematic.
Our findings do not suggest that AAPs should be banned in older patients with psychotic disorders. There are currently no safe and effective treatment alternatives in these patients. Short-term use of AAPs is often necessary for controlling severe psychotic symptoms. Also, specific AAPs in low dosages may be useful for longer treatment of certain patients. However, our results and other reports47
do indicate that considerable caution is warranted in off-lable long-term use of AAPs in older persons. Psychosocial treatments should be used whenever appropriate. Pharmacotherapeutic guidelines for “start low and go slow” should be followed along with close monitoring and medical management for metabolic side effects. Shared decision making, involving detailed discussions with the patients and their family members or legal guardians about the risks and benefits of AAPs and of possible treatment alternatives as well as of no pharmacologic treatment, is warranted1;35
. Clearly, there is a critical need to develop and test new interventions that are safe and effective in older people with psychotic disorders.