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March 31, 2013 by Sandra Steingard, MD

Optimal Use of Neuroleptic Drugs, Pt. II: The Monkeys Were Not Psychotic

I asserted previously that the impression of short term efficacy tends to be inflated. What I mean by this is that there is a general sense – within my profession and among the general public – that neuroleptic drugs are very effective. They are after all what allowed us to shutter our state hospitals. The folk narrative is that the main problem is not that they do not work but that people do not take them reliably so we should therefore put our efforts into getting people to stay on them.

I will review some recent studies that belie that belief. I have written about most of these before and the links are provided if you want more detail.Khin et al (Journal of Clinical Psychiatry 2012; 73(6):856-864)

  • This is a meta-analysis of data from new drug applications submitted to FDA from 1991-2008.
  • The researchers focused on the results of the PANSS (Positive and Negative Symptom Scale). This is a 30 item questionnaire that measures symptoms such as voices and delusions (so called positive symptoms) as well as apathy (so called negative symptoms). Each item is rated on a scale of 1-7 thus the score can be anywhere from 30 to 210 points.
  • At entry into the study, the average score was about 90 points.
  • The average decline in the PANSS in the active treatment group was 15 points and in the placebo group 6.4.
  • The effect size is the difference between these numbers and that is about 8 points. This was a statistically different effect but it is not one that has a major clinical significance.

Stefan Leucht et al (Mol Psychiatry 2009;14: 429-447)

  • A recent meta-analysis comparing second generation antipsychotic (SGA) drugs to placebo.
  • This includes 38 randomized controlled studies with a total of 7323 subjects.
  • There was an 18% difference in responder rates: 41% SGA versus 24% placebo.
  • The number needed to treat (meaning how many people need to be treated with the drug for there to be a benefit was 6 (CI: 5–7). This is considered to be a modest effect.

Meltzer et al (American Journal of Psychiatry 2011; 168:857-967)

  • This was sent out to every psychiatrist in America (I received at least three reprints) in support of the new drug lurasidone.
  • This study included over one hundred people in each group and it was conducted at multiple centers.
  • They compared two lurasidone doses to placebo and olanzapine.
  • The primary measure of efficacy was change in the PANSS.
  • On the PANSS, the lurasidone 40 mg group improved by 25.7 points, 120 mg by 23.6 points, olanzapine by 28.7 points, and placebo by 16 points.
  • These difference are statistically significant but of less clinical significance.
  • The overall difference between the olanzapine group and the placebo group was less than 13 points.
  • On the secondary measure, the CGI (Clinical Global Impression) a 7 point scale, the difference was less than half a point. That difference was statistically significant, but, once again, of questionable clinical impact.

Jin et al (Journal of Clinical Psychiatry 2013;74 (1):10-18)

  • Evaluated the efficacy of the 4 most commonly prescribed antipsychotics in individuals 40 years of age and older.
  • The authors reported , “no significant change in psychopathology with any of the study atypical antipsychotics.”

These are four large recent studies published in major psychiatric journals. The results are at best modest and at worse “sobering”. I was discussing this one day with a medical student. I told him about the Khin study but before telling him the results, I asked, “What do you think the reduction in the PANSS score would be based on what you have learned so far?” He guessed that in the active treatment groups there would 50% reduction in symptoms. He is a bright student and a 50% reduction is not a bad guess given that this would be a reasonable goal for a drug that is effective. In the Khin study, the reduction of symptoms in the treatment group was less than 20%.

The long term risks associated with these drugs tend to be minimized.

There are risks that are not controversial. This includes tardive dyskinesia, weight gain, and metabolic syndrome. For the sake of time and space, I am not going to review the data on this since I believe this is now accepted by my colleagues (although I continue to believe that it took about 10 years to be fully recognized due to the influence of aggressive and sophisticated marketing).

Robert Whitaker has highlighted other concerns including super sensitivity psychosis and brain atrophy. His most controversial claim is that people who remain on these drugs over time have worse outcomes than those who stop them. Martin Harrow’s recent article on this topic suggests that even this concept is beginning to be taken seriously within the profession.

Since these topics are so well covered on this website and in Whitaker’s books, I am not going to review in detail the studies that support these claims. I do not have much in the way of new information to add. I also do not believe I have the expertise in neuroscience to adequately address the question of neuroleptic induced super sensitivity of dopamine receptors. However, it seems that serious psychiatric neuroscientists consider super sensitivity to be a viable hypothesis.

Howes et al wrote a recent paper in the Archives of General Psychiatry (2012; 69(8): 776-786), “The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment.” This was a meta analysis of studies which evaluated the role of dopamine in schizophrenia. The main assertion of this paper was that pre-synaptic dopamine function is altered in schizophrenia. However, in their conclusion they write, “It is not surprising that when antipsychotics are stopped, when there is nothing to suppress the dysregulated pre-synaptic system and when there is a potentially supersensitive post synaptic receptor system, then there is a high risk of relapse.” (underline mine)

My point here is that a major research group mentions in passing in a paper published in an academically rigorous psychiatric journal (and I get it that some readers consider that an oxymoron) the possible influence of super sensitivity on increasing the risk of relapse when neuroleptic drugs are stopped. Yet those of us who raise this as a reason to moderate our use of these drugs are considered biased or scientifically naive.

Another point that I want to address is the issue of brain atrophy associated with long term exposure to neuroleptics. As noted in Anatomy of an Epidemic, Nancy Andreason’s group followed a group of people who came to them early on when they had first developed psychotic symptoms (Ho et al Arch Gen Psych 2011; 68(2):128-137). This was in the early 1990′s when researchers had thought brain atrophy was due to the psychotic condition. The thinking at the time was that early treatment with neuroleptics would arrest the process.

This is what led to the development of a number studies whose goal was to get people into treatment as soon as possible. The initial hypothesis of Andreason’s group was that individuals who remained on neuroleptics would have less brain atrophy but her study results did not support this hypothesis. They found that the neuroleptics themselves had a direct effect on the extent to which there was brain atrophy.

What is interesting is that this finding has not become as much a part of the mainstream psychiatric narrative as the original hypothesis. So to those who find it hard to believe that the drugs seem to cause atrophy independent of the psychotic process, I want to point out another study also reported by Whitaker. This is a study by Dolphe-Peterson et al. (Neuropsychopharm, 2005: 30(9): 1649-1661). This group gave haloperidol to macaque monkeys. They found that the monkeys had and 8-11% decrease in brain tissue after 17-27 months on the neuroleptic drug. The monkeys were not psychotic.

As noted above, in the early 1990′s there was a hypothesis that if neuroleptic drugs were started early the individual would have a better outcome. The time between developing psychotic symptoms and starting medications is called the duration of untreated psychosis. This will be the subject of my next blog.

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