Robert Whitaker: Dangerous in America

On his Mad in America blog, in a Jan 12 post Rethinking Brain Research in Psychiatry, Robert Whitaker, author of "Anatomy of an Epidemic," made the very legitimate point that brain studies on those with mental illness fail to account for the effects of exposure to psychiatric drugs.

Agreed. So, if you slice and dice the brains of deceased individuals with schizophrenia and bipolar and compare them to “healthy” brains, as scientists at the Scripps Institute very recently did, and find that DNA “stays too tightly wound” in the brain cells of schizophrenia subjects, is the effect attributable to the illness, as the researchers suggested, or to the meds the patients have been on all these years, as Whitaker argues needs to be controlled for?

Furthermore: If we can’t say for sure, is the study actually worth the paper it’s printed on? No to everything, says Whitaker most emphatically. “First, let’s look at this particular study,” says Whitaker, who then does not look at this particular study. What Whitaker fails to mention is the study’s real finding and its implications: that a certain gene regulation process observed in neurological disorders also has a correlation to schizophrenia.

The study, published in Translational Psychiatry, sheds very important light on the developing field of epigenetics, which is rewriting the entire book on genetics. If you haven’t heard of epigenetics, don’t worry - you will. I first reported on the topic back in 2004, when a PubMed search listed but one author researching bipolar from an epigenetic perspective. Now epigenetics is emerging as the main event. Last year, I heard Jonathan Sebat of UCSD talk about “copy number variants” in schizophrenia and autism.

Back to the study: The devastating effects of the acetylation of histones (which appears to drive the “tightly wound” DNA dynamic) is the narrow story. The insights the study sheds into the dynamics of epigenetics is the wider story. Both together add up to the real story. Here is the scientific gobbledygook from the research article:

The major findings from this study are: (1) histone ac-H3K9K14 levels are correlated with gene expression levels for several schizophrenia-related genes, including GAD1; (2) age is strongly negatively associated with promoter-associated histone acetylation levels in normal subjects and those with bipolar disorder, but not schizophrenia and (3) histone H3K9K14 levels are hypoacetylated at the promoter regions of important genes in young subjects with schizophrenia.

Maybe another group of scientists will discover that psychiatric meds are involved in the histone acetylation process, but a further study would require funding, and here Whitaker has his own agenda.

Whitaker says the researchers at Scripps could have “administered neuroleptics to healthy rats.” Huh? This was an epigenetics study, not a drug company pre-clinical trial. Does Whitaker even know the difference? Has Whitaker even heard of epigenetics?

“This is why I think it is time for the NIMH to reallocate its research dollars,” says Whitaker. “Decades of such brain research has not produced any notable therapeutic payoff.”

And it is an absolute certainty that there will be no payoff if propagandists such as Whitaker have their way. For there to be any kind of therapeutic pay-off, first we need to find out what is really going on in the brain. NIMH research has led the way in busting old myths (ironically, Whitaker relies on this research in Anatomy of an Epidemic) and has totally changed how we think about brain function and mental illness.

But it also reveals how little we truly know. Alas, there are no easy answers. All the low-hanging therapeutic fruit has already been plucked. Research is badly underfunded, especially with no short-term pay-offs in sight. Today's research efforts are for the benefit of future generations. That's what civilization is all about. We work, we sacrifice, for those who come after us. But there are no guarantees in the frustrating and noble quest for knowledge.

Figuring Out Schizophrenia - Part III

Yesterday was the last day of the International Congress on Schizophrenia Research, held in San Diego. A brief recap of my third day there:

Early morning: My brain has clearly not booted up, not even after two coffees. I sleepwalk into the main hall for a lecture on "The Hidden Life of Genes: Endophenotyping Schizophrenia," by David Braff of UCSD, the year's recipient of the Congress' prestigious William Warren Award (that's Dr Braff pictured).

I've already given you a major hint into endophenotype: Me, with bipolar, with major difficulty regulating my sleep, which seriously interferes with my ability to function. The general population also experiences sleep disorders, but clearly sleep is tied into my illness.

Thus, rather than look for illness-specific genetic needles in haystacks, it may be more constructive to seek out more common and obvious bio-markers (such as sleep) and work one's way upstream or downstream from there.

Dr Braff was writing about endophenotypes back in the seventies, but it is only within the last five years or so that the topic has really taken off. For instance, Dr Braff explains, patients with schizophrenia experience major problems in sensory gating, ie screening out irrelevant stimuli (such as a noisy ventilation system) which plays havoc with their ability to focus on relevant stimuli (such as a conversation).

What we are finding, according to Dr Braff, is a clustering of patients around various different endophenotypes (eye movement - saccades - involving reaction time is another). Thus, one drug is not going to fit all. The next generation of meds, he says, need to be far more specific.

Schizophrenia, Dr Braff concluds, is a malignant terrible disease that is not going to give up its secrets readily. Instead, we "have to conquer schizophrenia gene by gene, step by step."

Late morning: "Optimizing Cognitive Training Approaches in Schizphrenia," reads the title to this two-hour symposium. Translation: The brain is plastic. As Michael Merzenich of UCLA describes it, "Basically, we create ourselves."

The brain is born stupid, then evolves and becomes "massively optimized to fit into your world."

In recognition of this, a relatively new field is opening up that involves drilling patients in cognitive tasks we tend to take for granted, such as holding a thought in our working memory long enough to lay down new neural roadwork or responding to stimuli in a timely fashion.

New computer programs are being developed and being tested on patients, Sophia Vinogradov of UCSF explains, and we are seeing enduring changes in the cognitive performance of patients six months later.

Afternoon: Today's poster presentation has a treatment theme, and here there is a clear disconnect from the rest of the conference and earlier poster presentations. Pharma is out in force, with products based on 50s technology. An example:

I stop at a J&J poster testing Invega on a schizo-affective population. No surprise, the antipsychotic knocks out the psychosis. Invega is son of Risperdal, which in turn is a descendant of Haldol.

See what I'm driving at? The emphasis of current schizophrenia research is on cognition and the underlying biology. Psychosis is what gets patients in trouble, but difficulties thinking is what keeps them from winning back their lives. Pharma has nothing in its current inventory for this, but they're still in a state of denial pretending that they are still relevant. (Think Detroit, only not nearly as smart.)

So here is J&J, pitching a med with roots in the 1950s, with a study designed for no other purpose than to milk its current patent. I ask some of the other researchers about this and get a lot of nodding heads and knowing looks.

If only these researchers were running Pharma, I can only think. The good news: Everywhere, Pharma is clearly losing both its influence and credibility. The bad news: In another year or two, we are going to know J&J as makers of baby powder and other fine consumer products. Same with the other drug companies.

Where, then, are the new smart meds going to come from?

Much more in future blog posts ...