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)
Stefan Leucht et al (Mol Psychiatry 2009;14: 429-447)
Meltzer et al (American Journal of Psychiatry 2011; 168:857-967)
Jin et al (Journal of Clinical Psychiatry 2013;74 (1):10-18)
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.