Friday, February 10, 2012

Shedding Light on Brain Research: A Scientist Responds to Whitaker

Last week, I wrote a piece highly critical of a post Robert Whitaker published on his blog, Mad in America. His post attacked a very recent Scripps Institute study, which became the basis of his own editorializing on the research agenda of the NIMH, namely that “decades of such brain research has not produced any notable therapeutic payoff.”

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 ...

Hi, John

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 [5]. Another study found that clozapine and sulpiride could elicit small increases in acetylation of histone H3 [6]. 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 [7], 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.

Best wishes,

Elizabeth A. Thomas, Ph.D.
Associate Professor
Department of Molecular Biology
The Scripps Research Institute
3030 Science Park Rd, SP2030
La Jolla, CA  92037


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John McManamy said...

Thanks, David. Happy reading and looking forward to hearing from you. :)

Smitty said...

I'm still with Whitaker, John.

He hits many of the same nails on the head that I have, in my own private wanderings.

I am not convinced that those of us who are vulnerable to psychosis are that much different than anyone else out there who is normal. We just lost sleep, have emotional responses to blood-sugar imbalances, and/or triggering events in childhood. It is not in the genes, or at least not beyond a shadow of a doubt.

I do appreciate your inviting a guest author to balance out your rebuttal of Whitaker. Amen to you, you rock~

John McManamy said...

Hey, Smitty. I fully agree that psychosis does not equate to schizophrenia. Otherwise a hell of a lot of us would be diagnosed with schizophrenia. Also, a lot of weird stuff goes through the head that is psychotic-like but not actually psychotic.

The beauty of brain science is that it is making us rethink everything. The diagnostic labels are useful to a point, but they don't really tell us what is going on in the brain or why we behave the way we do.

But if we get stressed or there is a cognition snafu something biological is playing out in the brain, and we there are genes involved in that. And there is something switching these genes on and off, which is where epigenetics comes in.

And for human behavior, genes are about how we react to our environment. Epigenetics looks like it has a central mediating role.

A normal brain, normal thought, normal behavior - still genes, biology, environment, epigenetics.

So, yes I agree. Normal people just like the rest of us are vulnerable to psychosis (and anxiety and other stuff) through stress. The point Robert Sapolsky makes is that our genes do not cause certain behaviors or conditions. It's about influencing behaviors and conditions if and only if certain elements in the environment come into play. Stress is the big one. Poverty is the big stressor.

We're still learning. The whole paradigm is changing. Every idea is on the table. This is one reason we need lots more research. Something may come along tomorrow that changes the whole ball game. Everything is entirely different than when I came into this 13 years ago.

Keep disagreeing. But I actually think we agree. :)

Smitty said...

We probably DO agree more than we disagree.

But on the subject of epigenetics, beware. This has been studied for a lot longer time in other disciplines. It is not as well-charted or definitive as you may be hearing.

I am not for looking for answers in the genes.

If epigenetics gets us using common sense, great. My husband, who is a field microbiologist, wanting to solve real-world problems finds the epigenetic approach in his work just has people wowing each other with new "understandings." A little bit like guys jerking off, in his estimations.

He is usually spot-on about such things. He refuses to get stuck in the lab, studying things that don't have real-world impact.

John McManamy said...

Hey, Smitty. Perfectly agree. The topic is very new in bipolar, and when I first came across it at the end of 2003 only one researcher had published on the topic relating to bipolar. Suddenly, you are hearing the topic on the street.

I heed your cautions. I just finished viewing a 25-part lecture series by Robert Sapolsky. He covers epigenetics in one or two lectures. But in another couple of lectures he uses chaos theory to demonstrate that every time research gets close to something, the object of inquiry breaks up like a fractal into endless new repeats of mysterious patterns. In other words, research will never yield the definitive answers. Not only that, research raises more questions than it answers. But he does go on to say that the new questions that are raised are always way more interesting than the old ones.

I've seen this in my 13 years writing about mental illness. Granted my first few years I was fumbling along. But even accounting for that, the level of discussion amongst our community is far more sophisticated than 10 years ago. It doesn't mean we're any closer to the truth, but - holy cow! - you gotta love the conversations.

So, yes, I appreciate the "jerk-off" factor you mentioned. It's easy to get carried away with new stuff or flavor-of-the-month stuff. But I am looking forward to seeing how this plays out.

Anonymous said...

Hi John,

Love your site and your articles - I can't tell you how nice it is to find your work. Thank you.

Have you read Eva Edleman's book - Natural Healing for Bipolar Disorder? I see you have mentioned epigenetics a few times, so was also wondering if you have been in touch with or read Dr. William Walsh's research on epigenetics, undermethylation/overmethylation, copper/zinc imbalances, etc?

Take care.

John McManamy said...

Hey, Anonymous. Thanks for mentioning Eva Edleman's book. I will put it on my list. Also, many many many thanks for connecting some very important dots for me.

I am familiar with Dr Walsh's work. I meet him at the same conference I refer to in a recent blog piece. The over-under-methylation stuff was extremely interesting. But it didn't occur to me to connect his work to epigenetics until you brought it up.

If I am interpreting you correctly, the epigenetics research could wind up validating and building upon Dr Walsh's work, which means natural treatments could become a lot more targeted and effective.

This is one reason I am a very avid supporter of gene-brain research, and why the recovery movement needs to band together and press for much much more funding.

Anonymous said...

Dr. Thomas:
Regarding Hdac2 over activation, the Mount Sinai findings reported August 16, 2012, indicated that over activation in the brains of mice treated with atypical antipsychotics was found and, more to the point, in post mortem brains of schizophrenics treated with AA's, but not in schizophrenics who had not been treated.