My post noted that Whitaker had a point concerning one issue (namely, the need to control for the effects of psychiatric meds in genes-brain research), but that he had left out some critical information about the study and that his editorializing was way off-base.
You can check out Whitaker's post: Rethinking Brain Research in Psychiatry.
And my post: Robert Whitaker: Dangerous in America
Several days ago, I emailed Elizabeth Thomas PhD (pictured here), lead author of the study in question. I did not ask her to take sides. I simply directed her to both blogs (if she were morbidly curious about our food fight) and asked for points of clarification. Following is her response in full, published here with her permission ...
Thanks for your email. Yes, I was morbidly curious about your blogging battle with Mr. Whitaker and I did want to respond. Sorry this is long-winded…..
First to defend our work a bit. Like most researchers working with post-mortem brain tissue, we are aware that a confounding factor in post-mortem research on schizophrenia is the unknown effect of antipsychotic drugs, which are known to alter gene expression. (I have actually published two reviews on the topic of antipsychotic drugs and regulation of gene expression [1, 2]). It is an issue that cannot be avoided, as most if not all collected brains deemed “psychiatric” are due to information from a psychiatrist’s report and, hence that patient would be receiving some type of medication.
Just FYI, to address this in our research, we do typically do two things: 1) treat rodents with the drug in question, to look for effect on gene expression in the brain; and 2) perform correlation analysis between expression values in each human subject and the recorded drug dose of each subject. In our recent paper, we did provide drug information in Suppl. Table 1 for a portion of the subjects we studied; unfortunately, drug information was not available for the Harvard subjects.
Nonetheless, Mr. Whitaker is correct in that we should have discussed the potential effects of antipsychotic drug exposure in that paper, as we have in previous studies using post-mortem brains from some of these same subjects ([4, 5]). As it turns out, previous studies have looked at the effects of antipsychotic drugs on histone acetylation in rodent brain [5, 6], as Mr. Whitaker suggested should be done.
It was found that haloperidol, one of the most commonly used drugs, did not alter global histone acetylation in the brain, but could elevate a phospho-acetyl mark on histone H3 at a particular residue . Another study found that clozapine and sulpiride could elicit small increases in acetylation of histone H3 . Hence, the findings in our paper showing lower histone acetylation in patients, who in fact were treated with haloperidol or other D2 receptor antagonists, are unlikely due to drug treatment (if you want to use the rodent argument). I regret that we did not mention these studies in the current paper.
The finding that histone acetylation is lower at certain gene promoters is consistent with a lowered gene expression profiles for these given genes that have been observed in subjects with schizophrenia. On a whole, dozens of papers have shown that brains from patients with schizophrenia show substantial deficits in gene expression; this was the impetus for our studies investigating whether epigenetic mechanisms of gene regulation could be responsible and or contributing to this phenomenon.
Certainly, we cannot rule out that antipsychotic drugs could have an effect on gene expression in these subjects, but drug exposure is unlikely to explain the wide range of gene expression deficits detected. In any case, I do think Mr. Whitaker is correct about the importance of studies that would address the question of how psychotropic drugs may be affecting the developing brain, as many of these drugs are now given to younger patients.
Despite Mr. Whitaker’s claim that my response to our work was “the usual concluding pronouncement from such studies”, the reality is, in my opinion, that our findings provide a starting point to consider the only real new drug development for psychiatric disorders the field has seen in 50 years. Because we have shown that histone acetylation is lower in young subjects with schizophrenia, and that the acetylaton marks we studied are known to govern gene regulation, the use of compounds that could elevate histone acetylation (i.e. histone deacetylase [HDAC] inhibitors) could be useful to of restoring abnormal histone acetylation patterns and accompanying gene expression deficits in schizophrenia, leading to improved clinical outcome.
The possibility that these compounds could improve symptoms is supported by a recent study by Engmann et al., 2011 , who showed that the HDAC inhibitor, MS-275 could rescue cognitive deficits in a mouse model of schizophrenia. And further, that the mechanism for beneficial effects were via restoration of histone H3K18 acetylation deficits in the mouse brain. Other ongoing studies are testing other HDAC inhibitors in different rodent models of psychiatric disorders as well. (If my recent NIH application is funded, we will be testing novel HDAC inhibitors in a prenatal immune activation model of psychiatric disease).
As for your question about testing whether psychotropic drugs alter epigenetic pathways: There are two studies, as I mentioned above, that have been published, although the drawbacks of these studies were that only short-term treatments were used and epigenetic changes at specific genomic loci were not tested (only global levels measured by Western blotting).
A more important issue, in my opinion, is whether epigenetic drugs, such as HDAC inhibitors will truly represent a novel therapeutic avenue for psychiatric disorders. I would argue YES. New and improved HDAC inhibitors are currently being developed for various CNS disorders and my prediction is that they will also prove to be beneficial in treating patients with psychiatric disorders.
While it is expected that such compounds will have some “to be determined” side effects, they are unlikely to cause the same detrimental side effects of Parkinsonian symptoms and metabolic syndrome associated with the currently used antipsychotic medications. There is one recent clinical trial that has been completed showing improvement with valproate (an HDAC inhibitor) in schizophrenia, and several other trials are underway. (For more information see the clinical trial gov website). (Although it must be noted that the currently FDA approved HDAC inhibitors, such as valproate, are broadly acting compounds, unlike the ones in development, which would be more specific, hence less likely to cause unwanted side effects).
1. Thomas, E.A. Molecular Profiling of Antipsychotic Drug Function: Convergent Mechanisms in the Pathology and Treatment of Psychiatric Disorders. Molecular Neurobiology 34:109-28 (2006).
2. Thomas, E.A. Transcriptomics of antipsychotic drug function: What have we learned from rodent studies? Current Psychopharmacology, In Press.
3. Narayan, S., Tang, B., Steven Head, S.R., Gilmartin, T.J., Sutcliffe, J.G., Dean, B. and Thomas, E.A. Molecular Profiles of Schizophrenia in the CNS at Different Stages of Illness. Brain Research 1239:235-248 (2008).
4. Narayan, S., Head, S.R., Gilmartin, T.J., Dean, B. and Thomas, E.A. Evidence for Disruption of Sphingolipid Metabolism in Schizophrenia. Journal of Neuroscience Research 87:278-288 (2009).
5. Li J, Guo Y, Schroeder FA, Youngs RM, Schmidt TW, Ferris C, Konradi C, Akbarian S. Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J Neurochem. 2004 Sep;90(5):1117-31.
6. Dong E, Nelson M, Grayson DR, Costa E, and Guidotti A. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci U S A 2008; 105: 13614-9.
7. Engmann O, Hortobágyi T, Pidsley R, Troakes C, Bernstein HG, Kreutz MR, Mill J, Nikolic M, Giese KP. Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. Brain. 2011 Aug;134(Pt 8):2408-21
Finally, thank you for supporting NIH funding for basic and medical research in your blog – we are definitely in dire need and without continued funding, we will not be able to address these critical questions that could help patients with psychiatric disorders.
Elizabeth A. Thomas, Ph.D.
Department of Molecular Biology
The Scripps Research Institute
3030 Science Park Rd, SP2030
La Jolla, CA 92037