Thursday, October 11, 2012

Mental illness is complex too

Mental illness causes significant morbidity and mortality around the world but we know very little about its physiology or about how to treat it.  Yesterday was World Mental Health Day, so it seems appropriate to talk about this now.  A piece in Science last week addresses this issue* and the news isn't good.  The problems are multiple -- the brain is complex and difficult to study, it's hard to know which aspects of the functioning of the brain to focus on in trying to determine what goes wrong and thus how to make it right again, animal models may or may not be adequate stand-ins for human disease and drug response.  And, current medications are no more effective than drugs first used 50 years ago, but the problem is so complex that pharmaceutical companies find that it's just not cost-effective to invest in research into psychiatric drugs because progress is so uncertain.
"We just don't know enough,” says Thomas Insel, director of the U.S. National Institute of Mental Health (NIMH) in Bethesda, Maryland. “Research and development in this area has been almost entirely dependent on the serendipitous discoveries of medications. From the get-go, none of it was ever based on an understanding of the pathophysiology of any of the illnesses involved.”
This is no different from the story of most other complex diseases, of course.  GWAS and other genetic approaches have not provided any significant breakthroughs, even though, as with most complex diseases, the genetic hammer has been thrown at these disorders time and time again.  The basic biology is poorly understood (at best) so one hasn't much clue which regions of the genome to look at most intensely. Leads arise, excite,...., and then fade.  Knowledge of many psychiatric illnesses may be even more rudimentary than that of non-psychiatric illnesses: schizophrenia rates may or may not differ across time and place, autism rates may or may not be increasing, ADHD may or may not be a disorder.

As it happens, a $10 million study of the use of fish oil to reduce suicide risk in US soldiers was announced this week, as reported in multiple places including here.
The Medical University of South Carolina, the Veterans Administration and the National Institutes of Health announced the study of omega-3 fatty acids on Monday, which is being conducted for the U.S. Army.
In the controlled study, veterans already receiving mental health services will be given smoothies high in omega-3s for a six-month period. Others will be given a placebo.
"One of the questions this study hopes to address is do we see a clinical effect that is strong enough that the military would then consider providing supplements to all military personnel, not just those who are already experiencing depression," said Bernadette Marriott, a professor in the Institute of Psychiatry at the Medical University of South Carolina and the principal investigator in the study.
This might be laughable, really, given how much we know we don't know about mental illness.  Except that this kind of study presumably can be done empirically, without any real understanding of the pathophysiology of either depression or any possible effect of omega-3 on the disease.  If the suicide rate is importantly lower among those given fish oil than those given placebo, and that's really the only significant difference between the groups, it suggests fish oil might well be why.  Well, with all the usual caveats about confounders and so on.  And even if it's, say, the taste of fish oil rather than any effect on the brain, really, who cares as long as it works.

In the same vein, a September episode of the BBC Radio 4 program, The Life Scientific, with British psychiatrist David Nutt was a discussion of, among things, the potential for magic mushrooms, ecstasy, LSD, cannabis or mephedrone as treatments for PTSD or depression.  His group has published a recent paper in PNAS reporting a study of fMRI's of the brains of people on psilicybin, the active ingredient in magic mushrooms.  He was surprised at the results, he told Life Scientific presenter Jim Al-khalili-- he expected to see much higher brain activity but instead cortical activity was greatly slowed.  And, from the paper:
These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
Why?  If you read the "Discussion" section of the paper you'll see it is full of uncertainty about what these results are telling them or might mean; lots of mays, ifs and mights.  They do draw some conclusions; "Depression been characterized as an “overstable” state, in which cognition is rigidly pessimistic," pessimism has been linked to the areas of the brain in which this study found lowered activity in people on psilocybin, and brain "hyperactivity has been linked to pathological brooding."  So, the idea is that reducing brain activity might interrupt pathologically negative or self-destructive thoughts.

Of course, they also point out that "Further work is required to test this hypothesis and the putative utility of psilocybin in depression."  Again, this can be done empirically, and understanding the pathophysiology is not required.  But, fMRI's are not required either.  It looks as though Nutt had a hypothesis about these compounds having potential therapeutic utility, did the study and then constructed a hypothesis to fit the results.  But ok, no one knew how aspirin worked for a long time either.  And if these compounds work, if fish oil works, and actual progress can be made in treating mental illness, this could change millions of lives for the better, no matter how or why.

But, given what we know about complexity, we're betting there's no such simple answer to the problem of brain function and its variation and how to fix what can go wrong. 

*Science hosted a live chat on treating mental illness yesterday afternoon and it's archived here.

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