Antipsychotics in the Long Term: Zero Evidence

John McManamy Health Guide
  • Last week’s post, Antipsychotics Over the Long Term: Thomas Insel Weighs In, elicited 20 comments. First, a quick summary of the post:


    In his NIMH Director’s Blog, Dr Insel cited research in support of the proposition that, contrary to conventional psychiatric wisdom, antipsychotic medications may not always be a wise long-term option. According to Dr Insel:


    It appears that what we currently call “schizophrenia” may comprise disorders with quite different trajectories. For some people, remaining on medication long-term might impede a full return to wellness. For others, discontinuing medication can be disastrous.

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    Various schizophrenia treatment guidelines such as the one issued by the American Psychiatric Association advocate antipsychotic treatment over the long term, if not for life. The catch is that the supporting evidence is weak, or even non-existent. What psychiatry calls a long-term drug trial typically lasts six-to-12 months. There are no trials beyond two years. In other words, there are no long-term trials. None.


    Moving on ...


    The supporting evidence for the long-term treatment of bipolar disorder is equally underwhelming. We are told that relapse is common in bipolar, that we need to stay on our meds. But for how long? Especially if the med in question happens to be an antipsychotic.


    In the short term, to pull us out of a crisis, one finds little opposition to the use of antipsychotics. These are the miracle drugs that stop both psychosis and mania dead in their tracks, and there is no shortage of trials to prove it. Some of these agents even work as antidepressants.


    But pulling us out of crisis is a very different proposition than getting well and staying well, and here the studies don’t help us at all. According to the British Association for Psychopharmacology’s (BAP) Evidence-Based Guidelines For Treating Bipolar Disorder (2009), so-called “long-term” trials employ a “relapse prevention design.” The patients who enter these studies have first been successfully treated in a crisis situation, then are either kept on the same drug or given a placebo. 


    At this stage, the study has already been severely compromised. In the words of the BAP: “This enriches the sample for both efficacy and tolerability.” In other words, those who have not already done well on the test med have been weeded out of the study. Nevertheless, the BAP says these studies are useful if the clinician is looking to keep a patient on same med.


    Thus, the med that got you well (or at least out of crisis) may keep you well (that is, prevent a relapse). The BAP cites a 48-week study in support of this proposition (Tohen et al, 2006). At the same time, the BAP notes: “The excess of early relapse in this study suggests a contribution from withdrawal effects to the apparent effect size.”


    This is a very difficult sentence to translate. The BAP seems to be suggesting that some of the relapses in the placebo group could be attributable to the withdrawal effects of the med (in this case Zyprexa) rather than to the natural course of the illness. This is a problem that plagues long-term studies, and is well-known to clinicians and researchers. 


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    It’s funny that the BAP should cite this particular trial. A number of years ago, while researching the issue of meds compliance, I had a careful look at this very same study. According to the study:


    Compared to placebo, olanzapine [Zyprexa] delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.


    The study - funded by Eli Lilly, makers of Zyprexa - was published in a leading journal, The American Journal of Psychiatry. Any clinician checking out the article would have been encouraged by the results, namely: 80 percent of those in the placebo group relapsed compared to 47 percent in the Zyprexa group. In addition, the placebo group relapsed far more quickly (after a mean of 22 days) vs the Zyprexa group (174 days). 


    But we also have this unsettling result: Only 21 percent of the patients in the Zyprexa group actually completed the study (vs 6 percent for the placebo group). In raw numbers, only 48 of 225 Zyprexa patients were around at the end of 48 weeks vs 9 of 136 in the placebo group.


    Perhaps you can see the absurdity in attaching significance to any study with such an appalling completion rate. High drop-out rates are the bane of clinical trials involving psychiatric meds, especially when they go on more than the usual six or eight weeks. There are a number of statistical devices to compensate, but it is very difficult to make a case for that here.


    Yet the study was cited as evidence in a major bipolar treatment guideline.


    So, can a study like this actually tell us anything? If we look further, we find the doses were in the rather high range. Patients were put on flexible doses ranging from 5mg-20mg, but the mean daily dose was 11mg during the crisis phase and 12.5mg over the succeeding weeks and months. This begs the question: Would more people have stayed in the study had they been put on lower doses?


    Yes, meds overkill may be the preferred option to get us out of crisis. But common sense tells us that getting into recovery - where we actually feel well - requires a totally different meds strategy. I have no evidence to go on here, but then again neither do our doctors.


    Let’s turn to the wisdom of our community, here at HealthCentral:


    In response to last week’s post, Donna reports that Zyprexa has delivered her from decades of depression and hallucinations and worse. She gives this particular med “a LOT” of credit for her recovery. But pay close attention: “I'm taking Zyprexa about 2 days a week, and right now that's enough to keep me sane (enough.) I'm only taking about 1/4 of the prescribed dose on those 2 days. But it's working for me this way.” 


    Please don’t construe this as advice to do what Donna is doing. But it does seem that she has found a sensible middle way. If only someone would actually study this ...

Published On: September 15, 2013