Reading the book makes me feel liberated from the medical labels that are all too readily slapped on healthy people.  There is much that is healthy about sadness and many reasons and contexts in which its quite natural.  From now on, instead of trying to escape from, or rid myself of sadness, I will embrace it and let myself feel it and work through it.  Who knows, maybe this is a good first step in a healthy coping process.

If depressed emotional states are more a part of the normal range of emotions (rather than separate disordered states) then does this allow us to make predictions about the underlying genetic bases for these states?    Perhaps not.   However, on page 172, the authors apply their critical view to the highly cited Caspi et al., article (showing that 5HTT genotype interacts with life stress in the presentation of depressive illness – critiqued here).  They note that the incidence of depression at 17% in the sample is much too high – most certainly capturing a lot of normal sadness.  Hence, the prevalent short allele in the 5HTT promoter might be better thought of as a factor that underlies how healthy people respond to social stress – rather than as a drug target or risk factor for psychiatric illness.

In their forecast “The World in 2010” special issue, the Economist points to “The looming crisis in human genetics” wherein scientists will reluctantly acknowledge that, even with super-cheap genome sequencing tools, we may not soon understand how genetic variation contributes to complex illness.  The argument is a valid one to be sure, but only time will tell.

A paper I read recently, reminded me of the long hard slog ahead in the area of genomics and psychiatric illness.  The authors in “Association of the Glutamate Transporter Gene SLC1A1 With Atypical Antipsychotics–Induced Obsessive-compulsive Symptoms” [Kwon et al., (2009) Arch Gen Psychiatry 66(11)] are trying to do something very important.  They would like to understand why certain (most) psychiatric medications have adverse side-effects and how to steer patients clear of adverse side-effects.  This is because, nowadays, a patient learns via a drawn-out trial-and-error ordeal about which medications he/she can manage the benefits/costs.

Specifically, the authors focused their efforts on so-called obsessive-compulsive symptoms that can arise from treatment with atypical antipsychotic medications.  Working from 3 major medical centers (Samsung Medical Center, Seoul National University Hospital and Asan Medical Center) Kwon et al., were able to cobble together a mere 40 patients who display these particular adverse side-effects and matched them with 54 patients based on several demographic and medication-based criteria.  Keep in mind that most genetic studies use upwards of 1,000 samples and still – hardly – are able to obtain significant effects.

Nevertheless, the authors note that the glutamate transporter gene (SLC1A1 or EAAC1) is a most logical candidate gene, being a located in a region mapped for obsessive-compulsive disorder risk and also a gene that appears to be down-regulated in response to atypical anti-psychotic treatment (particularly clozapine).  A series of statistical association tests for 10 SNPs in this gene reveal that two SNPs (rs2228622 and rs3780412) and a 3-SNP haplotype (the A/C/G haplotype at rs2228622-rs3780413-rs3780412) showed modestly significant association (about 4-fold higher risk) with the adverse symptoms.

To me, this is a very noteworthy finding.  A lot of work went into a very important problem – perhaps THE most pressing problem for patients on anti-psychotic medications today – and the results, while only of modest significance, are probably biologically valid.  The authors point out that rs2228622 and rs3780412 have previously been associated with OCD in other studies.

But when you compare these modest results (that these authors fought hard to obtain) with the big promises of the genomic era (as noted in the Economist article), well then, the results seem rather diminutive.  Will all patients who carry the risk haplotype be steered away from atypical antipsychotics?  Will big pharma (the authors of this paper disclose a great many ties to big pharma) support the fragmentation of their blockbuster drug markets into a hundred sub-populations?  I doubt it.  But some doctors and patients will experiment and continue to explore this avenue of inquiry – and it will take a long time to work out.  Better check back in 2020.

pointer to: Information technology investor and member of the pioneering “PGP-10″ personal genome volunteer Esther Dyson has a great article on the Health 2.0 movement in – the mainstream of all mainstream media – the Financial Times.

pointer to — Dr. John Grohol, the CEO and founder of Psych Central, has a great post “You have the right to your health data” and introduces the Declaration of Health Data Rights,  a simple statement of fundamental patient rights.  Check it out and endorse!

Christopher Rowland gives a great perspective on the new venture fund at the Harvard Partners Healthcare system. If you want a peek at the future of personalized medicine, check out the Partners Center for Genetics and Genomics – where basic research is seamlessly integrated with clinical care. I attended their first annual meeting in 2005 and took home a lot to think about. This year’s meeting features Regina Herzlinger, who will discuss economic framework issues. I wonder if the Partners system is adopting or experimenting with new payor models … certainly the new venture fund will support research, but what about everyday clinical care?