Welcome to my blog, a place to explore and learn about the experience of running a psychiatric practice. I post about things that I find useful to know or think about. So, enjoy, and let me know what you think.

Thursday, May 28, 2015

More on the Ritalin-Induced Psychosis Study

I'm following up on my last post, I Don't Know What to Think. A friend (not the same one who sent me the Levine piece) had access to one of the full articles, and forwarded it to me. This is the 1987:

Prediction of Relapse in Schizophrenia paper, from Arch Gen Psych. Having read it, what they were trying to do makes more sense to me, but it's still problematic.

The paper's introduction comments:

...A major deficiency in the clinical management of schizophrenia is the lack of proven methods for predicting the subsequent course of illness and identifying those patients who require neuroleptic maintenance to prevent relapse or, alternatively, those who would remain stable for substantial periods of time without drug treatment or while receiving substantially reduced dosages.

There were some previous studies suggesting that behavioral response to psychostimulants could be used as a predictor of relapse. They chose ritalin because it preferentially inhibits uptake of dopamine, and they were trying to find support for the dopamine hypothesis in schizophrenia.

The reason given for conducting the study is:

The application of a psychostimulant provocative test using methylphenidate with stable schizophrenic outpatients undergoing neuroleptic maintenance treatment is an attempt to study whether it may be feasible to exploit this phenomenon for clinical purposes.

That's it. Vague, but it kind of makes sense. It's like a glucose challenge test. You want to know if a specific patient will relapse if you take him off his meds. So you do the ritalin challenge test, and if he responds in a certain way, you know he needs to stay on his meds. And if he responds another way, you can take him off. And what are those "ways"? That's what the study is trying to find out.

They gave most of* the subjects a ritalin infusion, and a placebo infusion, 1 week apart, in random order, while they were still taking meds. They did this in a double blind fashion. They rated the subjects before and after infusions for behavioral, physiological, and physical states and changes.
Then they repeated this process several weeks after discontinuing meds.

This is what the ratings found:

The white bars are before infusion, and the black bars are after.

You'll notice that while it was double blind, you can pretty much tell when the patient got ritalin.

Then they followed the patients for a year, or until they relapsed and needed meds again. And they looked at how response to ritalin infusion correlated with time to relapse. This is what they found:

Patients with greater behavioral and TD changes in response to ritalin, as well as patients with greater baseline TD, had significantly shorter times to relapse. Blink rate and pulse rate were not significantly correlated.

The paper does a bunch of additional analyses, with groups of symptoms rather than individual ones, to get more of what they wanted. But to me, the most interesting result is that patients with more baseline TD relapsed more quickly. That could be a useful piece of data, and it doesn't require a ritalin infusion.

There are technical problems with the study. It had very few subjects, there was a protocol change after the study had begun* (that's why some subjects only had infusions after discontinuing meds), and the paper was written before follow-up had been completed on all the subjects. Also, I can't quite figure out if they did an intent to treat analysis.

They also fudged a bit in the comments section:

...Specific biologic and clinical variables, including behavioral response to methylphenidate, presence of TD, blink-rate response to methylphenidate, and pulse rate response to methylphenidate, under specific pharmacologie conditions, are associated with outcome in terms of time to relapse following neuroleptic withdrawal. 

In the results, blink rate and pulse rate are not so associated.

Here's the ethical problem. Participation in the study could not possibly have benefitted any of the subjects. It only had the potential to do harm. It's not like the authors were positing that a ritalin infusion might delay or prevent relapse.

So I'm skeptical about the consent process. We're not talking about healthy grad students who volunteer to stay awake for 3 days in exchange for $10 and meals. Did the subjects really understand that participation was completely altruistic? That the results could only benefit others, down the road, and maybe not even that?

I would have felt better about it if the idea had been addressed. They mention in the methods section that patients were evaluated for ability to give consent. But I think that somewhere, the authors should have written about the fact that the study was designed in a way that would not benefit the subjects. And that a shorter time to relapse after ritalin infusion might imply a different subgroup, one that might have had a longer time to relapse if they hadn't been given ritalin.

What do you think?


  1. The consent form that I recall using from this era all seemed to specify that patients would either not benefit from the study or there was a detailed discussion of negligible benefits. The potential harms are also outlined. I can't imagine that the consent form for this trial did not specify exacerbation of psychosis as a possible complication.

    As an example, I was running a study at about that time. It was a study of a new antipsychotic and it did involve people going through a wash out period in order to take the new drug. The risk of exacerbation of psychosis due to discontinuation of the maintenance antipsychotic or lack or efficacy of the experimental drug was clearly outlined. Compared to the present research environment, the study at the time was done in an inpatient setting as well as an additional built-in safety mechanism. I think that many if not most studies today are done in outpatient settings for most of the study. It turned out the the antipsychotic in this trial was hepatotoxic and the trial was terminated.

    In my IRB experience, I had the impression that there is an emphasis on research subjects understanding that the goals of studies is the advancement of research that may or may not help them in the future but that the experiment would generally not be beneficial to them. That is also why there are usually no substantial financial inducements.

    1. I haven't done this kind of research, myself, so I'm ignorant. But I somehow assumed that most trials, of new meds, e.g., are a trade-off between the risk of getting into the placebo arm, or of the new medication not working, or of the new medication being harmful, vs. the possibility that the drug might work and might be helpful to you, as a subject. I thought you sign on knowing these risks, but willing to take them because there's a chance it might be helpful to you.
      That seems different, to me, than signing on to a trial that has no potential benefit for you, and may even harm you. I don't see how there was anything the subjects of this study could get out of being in the study besides the satisfaction of knowing they might help someone else in the future.
      Maybe the subjects did understand that some bad things could happen to them in the study, but nothing good could happen at all. I just find that hard to believe.

  2. Even in the case where the medication studied is known and available in the market like the study in the NEJM that looked at the treatment of chronic pain with levorphanol, the subjects will be told that they will be tapered off the medication per the protocol and will need to talk it over with their primary care physician. These consents are a major reason why it is difficult to recruit research subjects especially because you generally have to recruit subjects with known diagnoses who are probably already stabilized on medications. It is also a reason (in addition to many other selection factors) why most research subjects do not resemble the patients being treated in clinical practice.

  3. "...why most research subjects do not resemble the patients being treated in clinical practice."

    Thank you. That is a very important concept and one I've never thought about before in this area.

    And this from someone who in the past has explained to management about how the online surveys we hosted were skewed by the population that chose to answer them. Not that we didn't obtain valuable information from the surveys but they seemed to generalize the information obtained a great deal, especially when it supported one of their pet projects.

  4. It remains a bit hard for me to take Levine's comments seriously as his antipsychiatry bias is so ever-present [see here]. Likewise, Dr. Lieberman's justification for his psychostimulant studies is disappointingly vague as you point out. For one thing, it was a time when the question of dopamine was on the front burner. One thing that occurred to me was if there had been a consistent response in the study in either the whole group or some identifiable subgroup, it might had lead to a repeat study in those patients that are suspected to be "prepsychotic" to see if it might predict which ones really were going to develop a psychosis - but that's just a passing thought.

    I don't know why Lieberman was President of the APA. I'm not a member either. I certainly second what you said in the earlier post, "... I also don't equate the APA with psychiatry". George Dawson's comment on your previous post " President of the APA is basically an anointed position" is surely right [as are his other comments there].

    I don't think Levine's logic:
    --"Lieberman is a Nazi"
    --he was "President of the APA"
    ----ergo "psychiatry sees nothing wrong with these psychotic symptom exacerbation and provocation experiments"
    ----ergo Psychiatrists are Nazi Sympathizers, or uncaring people, or both.

    This isn't going to win him any prizes in a logic contest. From reading his other articles, he generally starts with conclusions [or should I say, the monotonous conclusion that psychiatrists are jerks or worse] and works his way backwards.

    I appreciate your looking back at Dr. Lieberman's articles and letting us know what they were about.

    1. I don't take Levine's comments very seriously, either. But it was worth looking at the studies. There's a follow up study published in 1994:


      I can't figure out if it's the same study but with complete data, or a separate study. They do postulate that there's a subgroup of "dopamine sensitive" (my expression) patients who relapse faster than others, have more severe baseline TD, and respond more intensely to ritalin infusion. But if that's the case, the study design makes no sense, because they just redo the same protocol of challenging with ritalin and then taking them off meds.

      What they needed to do was take them off meds, NOT give them ritalin, see who relapsed faster, and then look at that group separately. Because it would actually be helpful to know if there are distinct group responses. And their design doesn't show that, nor does it rule out the possibility that if such a subgroup exists, they might relapse faster if you give them ritalin than they would if you don't.

      You know a lot more about study design than I. If you get a chance, can you tell me what you think?

      And George, if you're reading this, that goes for you, too.

  5. "I thought you sign on knowing these risks, but willing to take them because there's a chance it might be helpful to you."

    I'm not sure what sold these people on joining this particular trial but there are multiple reasons someone might sign on to them. I've been in two; none for psychotropics or mental illness.

    The first one I joined only for the $400 and the free diagnostics that went with it. I had zero expectation the med would help me and even if it did I would not have been able to stay on it due to the point it was at in the research. It made me worse and I dropped out but not before reaching the $400 milestone. The second one was more straightforward and more in line with your thinking. It was for a vaccine my employer was unwilling to pay for but it also included a monetary enticement and a titer to guarantee immunity.

    If I was eligible to join more drug trials, I would. I know there are some real issues with them and the outliers are horrendous but the best care I've ever received from the healthcare system has been within a drug trial.