Too good to be true? Aspirin and schizophrenia.

A t the heart of designing clinical trials is the notion of minimizing the role of chance. This is done by various means including randomization and the careful choice of control groups. A null hypothesis is then generated that states that there is no statistical difference between the experimental groups. The clinical trial’s goal is to reject the null hypothesis such that we can conclude that treatment A is statistically better than treatment B. Another factor is that results should be reproducible or verifiable. When replication supports the outcome of a trial, there is greater confidence that the results of these trials support a real difference between the experimental groups. An important caveat here is that a reproducible statistical difference between 2 treatments does not imply a clinically meaningful difference between the 2 treatments. I firmly believe that the job of the clinical trialist is to do everything possible in the trial design to find ways to refute the trials findings. The late Karl Popper argued that we cannot accept a result or theory as scientifically valid unless there is a possibility that it can be shown to be invalid. Recently, there has been a dearth of new chemical entities developed for the treatment of psychiatric disorders. Rather, in this vacuum, we are seeing an increase in trials of natural products or common substances such as omega-3 fatty acids or aspirin. Wouldn’t it be nice if we could change our diets or take commonly used substances and positively affect psychiatric disorders? A currently popular underlying hypothesis is that inflammatory processes play a role in etiology or manifestations of these disorders. As I read this literature, it is not always clear to me which of the following is being asserted: (1) inflammation in utero or in early childhood is a risk factor, or (2) current or perhaps chronic inflammation is a determinant, or (3) both contribute. With all of the above in mind, I recently reread an article on aspirin and schizophrenia. I admit to doing so with a degree of skepticism. I was looking for what is called type I error or a ‘‘false-positive’’ interpretation of results. My skepticism (or perhaps bias) is also fueled by my years as a clinician during which I treated quite a few patients with schizophrenia who also had concomitant conditions such as injuries, headache, or arthritis and took aspirin for extended periods. During these exposures, I did not see improvement in their psychopathology. Rather, these unwanted conditions caused some patients to become more symptomatic or regressed. The thoughtful reader may well say that this observation is irrelevant as it is not the same as giving aspirin to patients who do not have concomitant conditions. I do not disagree; I bring it up to show how one must be very clear in stating one’s theory. I assume those who would argue for a role for inflammation are assuming a subclinical or localized situation. Now to the article by Laan and colleagues for a closer look. This is an interesting and provocative paper claiming a clinically meaningful benefit for adjunctive aspirin therapy. However, because I am looking for type I error, I first looked at the outcomes of the 2 treatment approaches. Both groups contained patients being treated with olanzapine, clozapine, or risperidone. The distribution of these 3 drugs was different in the 2 cohorts. This could be an important point, and I will return to it later. The outcome scale used was the Positive and Negative Syndrome Scale. The decrement for the aspirin group after 12 weeks was 4.86. For the ‘‘no aspirin’’ group, it was 1.57. In my opinion, this betweengroups difference of 3.29 scale points, although statistically significant, is not clinically significant. Patients can score between 30 and 210 on the Positive and Negative Syndrome Scale. It is also interesting that just time alone was associated with a 1.57-point decrement for the ‘‘no aspirin’’ patients. There is also no assurance, given the 3 drugs involved, that each was titrated to its optimal dosage level or used for an optimal duration. Duration of illness is provided in the demography for these patients; duration of drug exposure is not. Because a gram a day of aspirin can cause gastric bleeding, all patients were given the proton pump inhibitor, pantoprazole, to reduce gastric acidity. This was a wise precaution taken by the investigators. However, the investigators did not take into consideration the fact that pantoprazole use would have an effect on the ionization of the drugs involved, and the impact of any differences EDITORIAL