To leave me here on shaky ground

So, five years ago, I wondered if the delays in approving, and obstacles in administering, drugs like clozapine (Clozaril) could actually be used to hold parties liable for deaths that occurred while deserving patients weren't getting their meds.

This was kind of a thought exercise, as I understand it would be extremely difficult to measure. But I thought the notion of holding administrators, bureaucrats and lawyers as accountable for their decisions as physicians was one worth exploring.

So I was intrigued to reports of a new study in the Lancet that started like this:

"Thousands of people with schizophrenia worldwide could have been saved if doctors had prescribed them the anti-psychotic drug clozapine, a new study says."


This was the largest study yet to look look at mortality and antipsychotic use. The authors' aim was to examine the mortality gap between the general population and those with schizophrenia, on or off meds. The accompanying editorial phrased the study's findings succinctly:

"Tiihonen and co-workers address a crucial question—to what extent do second-generation antipsychotic drugs contribute to excess mortality in people with schizophrenia? This question has loomed large since reports of raised risk of weight gain and diabetes associated with some of these drugs. Even the earliest studies of weight gain and incident diabetes suggested substantial heterogeneity across second-generation antipsychotics for adverse metabolic effects. Subsequently, large clinical trials, including the CATIE study, have confirmed that different drugs have different metabolic liabilities. Now, differences in mortality also seem to exist between drugs. In today's study, current use of quetiapine was associated with the highest risk of death, with a hazard ratio of 1·41 (95% CI 1·09–1·82) compared with current use of perphenazine. Current use of risperidone was also associated with a (34%) increased risk of death, compared with current use of perphenazine.

Analyses of cumulative use of antipsychotics did not show an increase in cardiovascular mortality in patients taking olanzapine and clozapine over the 11-year study. This finding is surprising in view of the substantial evidence of heightened cardiovascular risk associated with these two drugs. Clozapine was, in fact, associated with a much lower risk of death than was any other antipsychotic treatment, and a substantially lower risk of suicide than with any other medication. Even though people with clinically significant medical comorbidities might be excluded from clozapine treatment and the eventual burden of cardiovascular mortality could take decades to emerge fully, this finding is still striking. Furthermore, these results mean that the reports of under-use of clozapine in African–American patients with schizophrenia are of even greater concern."

The authors make a suggestion:

"...our results raise the issue of whether clozapine should be used as a first-line treatment, because it seems to be the safest antipsychotic in terms of mortality and it is also the most effective.

However, clozapine is inexpensive, and hence it is unprofitable for the pharmaceutical industry to market compared with other second-generation antipsychotic drugs. Additionally, monitoring schedules are a drawback that would be encountered with heightened use of clozapine,and physicians and other hospital staff might therefore be reluctant to initiate clozapine treatment. However, clozapine is associated with a lower discontinuation rates than is any other antipsychotic, and monitoring is not likely to be a major difficulty for patients after the initiation of treatment."

So, after all these years, even with the much-emphasized risk of agranulocytosis and weight gain, clozapine is the safest atypical antipsychotic? At least, in Finland? I'm no psychiatrist, and the only time I order atypicals are when I'm caring for boarded patients already taking these drugs. The docs over at Furious Seasons seem appropriately skeptical.

Still, it's interesting that the media is making this leap, and framing the study in terms of 'lives that could have been saved' -- a step the authors and editorialists weren't willing to take, and one that I don't recall seeing during the news from, say, the WHI hormone replacement reversal. It's an interesting way to frame results because, unlike 'number needed to treat' or 'likelihood ratios,' 'lives that could have been saved' implies liability -- not just for doctors but for bureaucrats and drug marketers. It's a metric that lends itself well to ... thought exercises.

Via @PharmaGuy (forum post)